 So thank you so much for joining us tonight or today on ethical frontiers and biotechnology. This is a multi lecture series that I've developed at Harvard Medical School through the Center for Bioethics. And tonight we're going to talk about what are called multi-cellular engineering living systems or M cells for short. So this is a series that's meant to bring both ethicists and scientists together to talk about emerging ethical issues and emerging biotechnologies. Tonight I'm honored to have my co-host, Dr. Roger Cam from MIT. But let me just introduce myself in case you don't know me. My name is Im Siu Hyun and I'm a professor of bioethics and philosophy at Case Western Reserve University School of Medicine. I'm also on the teaching faculty at the Center for Bioethics at Harvard Medical School and I'm a senior lecturer at Harvard Medical School as well. Let me turn it over now to Roger. Roger can just introduce himself briefly and then we'll get into our program. Roger. All right. Thanks, Im Siu. Let's see. Do I want to share? I'll share my screen in a second. You can just speak right now. That's fine. Yeah. OK. So I'm Roger Cam from MIT. I'm in the Biological Engineering and Mechanical Engineering Departments. And I'm also the director of an NSF-supported center on emergent behaviors of integrated cellular systems, which is kind of the parent of what I'm going to be talking about today, which is on multicellular engineered living systems. So my background is as a mechanical engineer in fluid mechanics initially. And I helped organize the Biological Engineering Department at MIT and have been a member of both the Biological Engineering Department and Mechanical Engineering for the past 20 years. And I've done NSF for several years now and very much enjoyed working with him. I'm looking forward to the presentations today. Thank you, Roger. OK, so let's get into our program brought to you by Zoom. And normally we have this at a lecture hall or a lecture room at Harvard Medical School. But now because of our current situation, obviously, we're going to present this to you through Zoom, which allows us to actually reach a much bigger audience beyond the Harvard Medical School immediate vicinity. So let me go ahead and share my screen and I will, my slides, and I will go ahead and launch into the program. All right. So as I said, this series is called Ethical Frontiers in Biotechnology. And tonight we're going to be talking about multicellular engineered living systems. That's quite a mouthful. So we're going to just call them M cells for short. These are really pretty interesting and new entities. And often when one is confronted with this, one may wonder, what is it exactly that's in the dish? The schedule for today is to first talk about what are these multicellular engineered living systems? And Roger will start us off with that with some of the science behind this. Then we'll switch over to me and I'll introduce the concept of bioengineering ethics and why that may be useful and relevant for this field. We're going to switch back to Roger. And Roger's going to talk about some current examples and the future potential of M cells. And then I'll bring us down the home stretch with talking about how we should promote the socially responsible development and application of M cells. And of course, then after that, we will spend quite a bit of time fielding your questions through the chat function. So as we're speaking along the way in our presentation, if questions come to mind, please enter that into the chat function field and send that along. And then at the end, we'll try to cover as many of these as we can. OK, so I think with that, I'm going to turn our right back to Roger. And Roger can then take over with bullet point number one. Stop by share. OK, I will share my screen. OK, can everybody see that OK? Yes. So a lot of what I'm going to be talking about today are called micro physiological systems. And these are systems that mimic certain aspects of physiology or biology, typically on a microfluidic platform. And I know some of you may not be familiar with microfluidics in general, but the concept is really very simple. We use a device, something like this, it's sketched over here, where we can insert in the pink region here cells that are suspended in, for example, a three dimensional matrix. So for example, in the image on the right, I suspended endothelial cells with fibroblast cells into a matrix. And then we have access to lateral channels that we can use to either control the environment of those cells, feed them, produce flows, produce concentration gradients. And we recapitulate a lot of the types of the type of experience that the cells have when they're in the body in vivo. And one example, I'm going to be talking a lot about emergent behaviors and how cells intrinsically have the capability of forming into three dimensional structures. And an example that I like to use to demonstrate this is on the right hand side here. These are the cells that have just been suspended in the matrix. And on the next slide, I'm going to go to a full screen view where you can see what these cells do over a 24 hour time lapse period. And what you see is that the cells, because these are endothelial cells, they want to form vascular networks. And the vascular networks are formed by the cells not so much migrating, but they actually send out projections toward their neighbors. And by the end of this 24 hour period, those vessels have actually started to form. In another four days after this time, those vessels are per feasible. And we can then start to refuse things like organs or look at situations such as metastatic cancer is that we've done a lot of work on in our lab. One, as we start to make these systems more and more realistic physiologically, one of the things that we've been doing is to try to mimic the microvascular mature that you have in different organs. And here what you see is some work that we've done in taking three different cell types from the brain to look to see whether we can reproduce the types of behavior that you see with the microvascular mature in the brain. And the reason we're interested in that are several. One is that we'd like to be able to understand better how things like drugs get from the vascular mature into the brain tissues for treating diseases like Alzheimer's, Parkinson's, various other cancers, brain cancers, and different neurological diseases. But also just as a general physiological model to better understand how the brain ultimately works. This model currently doesn't have neurons, but one of the things we can easily do is now to start to use these vascular networks to refuse clusters of neurons so that these neurons can actually survive longer time. So here what we do is we take these three different cell types, astrocytes, pericytes, which tend to wrap around the vessels. And then the endothelial cells that form the vessels themselves, we inject them into the central gel region inside of matrix. And then over a period of about four to seven days, they form what you see here, the green cells are the endothelial cells that are forming the vascular network that we can refuse through. We refuse media through them. And the pink cells are astrocytes, which are taking on a conformation and a morphology that's very similar to what you see in the brain. If we were to compare this image to an actual image in, say, a human brain, for example, we find that they appear very similar in terms of dimensions and density and so forth. We also looked a lot at the functionality of these networks. So one of the things we measure is how leaky these vessels are. And a measure of that leakiness is the permeability, which I'm plotting over here on the right-hand side. And here what I show is that due to the interactions between the different cells, as we go from, first of all, just the vascular cells and cells, the endothelial cells, all these cells, by the way, are human-derived. These are IPS-derived endothelial cells. They're fairly leaky initially. And the networks, I don't have a picture of them here, but they don't look like brain microvascular chirps. But as we start to add the other cell types that are present in the brain, here we've had the pericytes, and here we've added the pericytes and the astrocytes. The functionality in terms of the permeability of these vessels gets better and better. And when we have the triculture system with the pericytes and astrocytes combined with the endothelial cells, we actually get down to permeabilities that are pretty comparable to what you see, for example, in measurements in animals, in this case, in the rat green. You can also see that these vessels become more brain-like. So the vessels that I'm forming are from IPS-derived endothelial cells. And of course, IPS cells don't know, and they're obtained from the skin, for example. They don't know anything about the brain. But when they're co-cultured with the brain cells, in this case, either the pericytes or the pericytes and astrocytes, they start to take on a phenotype that is characteristic of what you see in the brain. So for example, these first three rows correspond to type junction proteins. And the type junction proteins tend to be more highly expressed in the endothelial cells in the brain, in microvascular during the brain. And here you can see that happening through the immunohistochemistry images that I show, three different junction proteins. Another thing that happens is the basement membrane tends to be better developed in the brain relative to other organs. And here you can see that through staining for laminin and collagen type 4. Those are sort of qualitative measures, but here we can do RT-PCR. So if you look at day seven of the co-culture, for example, you can see as you go from an IPS drive endothelial cells to the co-culture and the triculture, again, these three junctional proteins that I've indicated here in green, they all get up-regulated relative to the co-culture, the monoculture system. As do a number of these other things, that these proteins that I've indicated with the red arrows, these are transporter proteins that also tend to be up-regulated in the brain. And again, we see that in the triculture system, because of the signaling between the cells, these are also up-regulated. And then switch to a different system here. Here's a model that we developed as a three-dimensional model, in the sense that it replicates the three-dimensional geometry and morphology in the brain of a motor unit. And we're using this to develop a model for ALS, so that we can use it as a drug screening platform for ALS. And here it's a somewhat more complicated system than I showed you before, but really all that we do is we insert into one chamber muscle cells. These muscle cells over time form a muscle strip that's suspended between two posts. And the reason the posts are there is so that we can measure the forces that are generated. And then at a later time point, separately we're differentiating ES cells, embryonic stem cells, into motor neurons, in a motor neuron neurosphere, the spherical collection cells, that we inject over here in matrix. And then over the next several days, these neurites extend out from the neurons, connect up with the muscle and form a complete neuromuscular junction like you see here. And this is what it looks like in reality. Again, these are fluorescently stained cells, but you can see the cell API over here, the motor neurons that are derived from either induced flurry potent stem cells or ES cells. And then also the muscle strip over on the right-hand side. And I just realized that I've gotten a little bit ahead of myself. What I wanted to do here is also go back and say a little bit more general about what M cells are, because I realized that this audience probably is not very familiar with that. So let me come back to that. But in the meantime, I wanna talk a little bit more about the multicellular engineered living systems that N-SU is talking about. These are simply systems that are formed from multiple cell types that we can drive, for example, like you're seeing from induced flurry potent stem cells. Here, for example, our muscle cells, myocytes, neurons and endothelial cells. And with M cells, we're engineering these systems to produce either a functionality that already exists in vivo or one that doesn't. And by that I mean sort of a non-natural organ function. But we can assemble these in some way to produce a system that may have sensors, may process information from the sensors, and then may have some sort of effectors. So these could be muscle cells, they could be cells that secrete something. And what we've been doing through our NSF-supported center is to try to develop a quantitative understanding of these multicellular living systems that have some sort of defined and pre-prescribed form and function. And we've argued that we really have to establish a more fundamental understanding of these cell-cell or cell-matrix interactions. And then be able to control those through biochemical, genetic, electrical, mechanical cues in order to promote their emerging behavior to produce a complex cellular system of our design. So there's been a lot of developments in the last 10 years I'd say that are related to what I'm talking about tonight. One is obviously the success of IPS cells to be that you can differentiate into a variety of different somatic cell types. And that work started really by Yamanaka back in 2006. You saw, you may have seen the presentation from Jinping Fu or Paula Arlada. I guess she's coming up next actually as a speaker. But a lot of work has been done in developing these organoid structures. These date paid back to about 2013, 2011, where both liver and optic cup were developed. And then later for organoids now for a number of different organs, and especially a lot of interest has been focused on these organoids for brain. I'll come back to that just a little bit at the end. The other development is that people have developed these what are called organon chip models where by engineering cells and by putting them within either some sort of a structure or even taking organoids and starting to develop those into organon chip models. We can now have brain, lung, bone, tumor, other organ-like systems that either can operate individually or can even be interconnected. And there's been a lot of work recently supported by DARPA to actually put 10 different organs on a single platform that can interact with each other and therefore start to replicate some of what happens in human physiology through interacting organs. So the organoids are, I guess, what I would call the most emergent structures that we have. The sort of intermediate, another area of interest for us in M cells are what are called the microphysiological systems that I mentioned. These are based on microfluidic platforms, different cell types, different matrices. These are largely engineered systems. And then biomachines is another area of interest in our NSF center. I'm not gonna talk too much about those tonight, but these are really autonomous machines. They're not in a microfluidic device and their form is really engineered and imposed by that structure. And the emergence comes about here in the context of how these cells interact with the use of a machine-like action. So in terms of designing and fabricating M cells, you could think of different approaches. In one approach, actually in both approaches, we start with having to have some sort of a design in mind. And then when we think about based on that design, if this is, say, a pump or a sphincter or a valve of some sort, what cells need to be used in order to generate this? So as an engineer, as a mechanical engineer, I might think more of along lines of a top-down engineering approach. First of all, differentiate the cells into neurons, muscle, and endothelial cells. Then I might form the structures, the muscle strips, the vessels, the clusters of neurons. And then I'd put these together in order to make the ultimate design that, in this case, like I was saying, maybe a neuron-driven set of muscles that could be used as a pump in the body. And that's what we call the top-down engineering approach. The alternative is more what we would like to call an emergent engineering approach, where we start with the same design. We still have to ultimately get the same cells. But here, rather than going through the engineering assembly process, we let the cells do the self-assembly. So we might start with a cluster of pluripotent cells, co-differentiate those through various mechanisms that I'll show in the next slide, so that we get the endothelial cells, the muscle cells, and the neurons, and then induce them to self-organize into ultimately the same structure. Realistically, what we do today is kind of a mix between these two. We use some top-down engineering approaches, and then certainly the emergent properties of themselves take place to help us form these machines. But what we've been working on in our NSF center is to try to understand this process and allow us to be able to do and go through an entirely emergent engineering approach. One of the important steps in that process is to take these cells in subplusters and then start to differentiate them into the different cell types in a spatio-temporal manner. So we might use biochemical factors to generate neurons over here, or we can use light activation by optogenetics of different signaling pathways in the cells to induce certain cells to become endothelial cells, for example, can use electrical stimulation, mechanical force, a number of different methods that we might use in this emergent engineering approach. And then finally, once we understand these processes better, ultimately we'd like to use these to generate systems that have useful applications. So we have to think about how these M cells will be manufactured. I'm not gonna go through the details of this, but they're pretty much the same processes that one thinks about. As a design engineer or a manufacturing engineer, how do you go from, say, the raw materials, setting up design, starting to develop different fabrication methods? Bio-printing, for example, has been very instrumental in terms of enabling us to start to produce these living structures. And then we have the manufactured product, and then of course, if that's gonna be marketed and used for flux screening, for example, or other applications, there have to be a number of approvals and assessments and other processes that we have to go through. So again, just the concept of emergence, which times a little bit foreign to people. I'd like to give this example of the MIT Cheetah, where there's no emergence at all. It's completely self-assembled by the engineer, non-biological, no emergence, and it follows pretty well-established principles. The motor unit that I was starting to show you a few minutes ago, certainly we have to form the motor neurosphere, we form the muscle, there's some assembly required, but the emergence between the individual cells is really critical here. And we don't understand this well enough to be able to predict the performance very well. And then if we go to something like the brain organoid, where everything is self-assembled, emergence is everything, we can't really control how the structure forms and we can't predict its performance very well. So that sort of covers the full spectrum. So at this point, that's kind of an introduction to themselves. I'll come back to give, talk about the example some more in a little bit, but now I'm gonna turn things over to Insu. Thank you, Roger. So if you stop sharing your screen, I'll get mine. Thank you. Okay. So Roger did a wonderful job giving you an introduction to what M cells are and what we mean by M cells. What I find fascinating about them from a bioethics and ethical point of view, philosophical point of view, is a very idea that you can engineer constructs that are multicellular, mammalian cells, human cells, and that you can try to design them in a way to leverage their emergent properties, as Roger just briefly explained, leverage those emergent biological properties for engineering goals and ends and purposes. So really define human tool-like purposes. Now, when I think about the ethics of this emerging, very exciting area of work, I think it would be helpful to try to approach it from a new angle. In the past, we've had traditionally bioethics and engineering ethics. I think that we need something in between those two, something that I'm gonna call bioengineering ethics, because traditional bioethics has plenty of tools to address ethical issues in research, but they typically are shaped and developed for the context of human subjects research or drug development, research on entities that are natural kinds, right? So animals, human beings, genomes, things that you find in the furniture of the world, things that you find in nature itself. But what Roger has shown us is that there's plenty of interest in creating things that are non-natural kinds, things that do not on their own appear in nature but need a nudge, they need a designer, they need an engineer to come into existence. Now, engineering ethics traditionally conceived didn't bother itself much with living matter, with cells, with stem cells, with multi-cellular systems. Engineering ethics normally bothered itself with things that are completely, like the MIT cheetah, completely engineered from non-living matter, steel, wires, computer chips. So we need something in between that to deal with this new space. It's gonna lie somewhere in between traditional biomedical ethics and engineering ethics. So how do we carve out this space? And this is an area of active interest of mine. It's an area that I think deserves further exploration. And I think it's definitely a growth area in bioethics for people up and coming who need a career. What distinguishes this from many other traditional forms of ethics is that it's very collaborative. You have to have input from both scientists and ethicists to co-create or to even use the terminology that biologists like to use to co-culture these two approaches at the same time in a way that's mutually reinforcing and mutually influencing. So I'd first propose this type of in-between ethics between traditional bioethics and engineering ethics in a paper that I published in cell stem cell back in, I believe, was 2017. And there the title of it was engineering ethics and self-organizing models of human development, both the opportunities and challenges. So let me explain a little bit further what I mean by engineering ethics. What is this new engineering ethics? As I said, traditional engineering ethics had to do with non-living things. But let me expand further though. Traditional engineering ethics seem to be very much focused on the ethical and social implications of new technologies before technology design and formation just kind of an anticipation of how much the world might change if we unleashed a new technology in social life. So think of autonomous driving cars here, right? So people will think before they actually exist, how will society look with autonomous cars and how might that affect industry like trucking and other economies based on human drivers? And then you have another area of engineering ethics which looks at how to assign blame when things go wrong. So the Challenger explosion and the space shell is a very good example of this, right? When things go wrong, how do we assign blame and how do we prevent things like this from happening again or when a bridge collapses, the same thing happens? What's missing is that sort of middle portion of the development of the technology, the ethics of the development and design of a new technology. And that's where the new engineering ethics comes in. Now the new engineering ethics in that sense of the ethics of design, the ethics of design engineering and technology development itself has really emerged out of the Netherlands. There's been just beautiful, wonderful work in this so-called new engineering ethics coming out of the Netherlands. And I'll just use a simple example to explain some of the insights of this approach. For example, the Dutch Evo Car was a project where design teams were challenged to come up with a design for a city car for cities like Amsterdam where you wanted to do two things. You wanted a car that was extremely efficient but also a car that was extremely safe. Now design teams when they were launching into this project realized very quickly that those two goals, efficiency and safety, fight each other a little bit. You can't optimize both goals at once. You have to trade off one for the other at a certain point. The heavier you make the car by making it safer by adding more safety features makes it less efficient. To make it more efficient, you have to make it lighter. And so you realize you can't actually maximize both engineering goals at the same time. So you have to make a trade-off decision and when you make these trade-off decisions you can possibly depend on values. Some of these values will be ethical values. There'll be values and questions like this. What do we mean by safety? Do we mean just the safety of the driver and the passengers? Or do we also mean safety of the pedestrians? What do we mean by efficiency? Do we also include in that sustainability? So these are deeply social and ethical questions that depend on commitments for ethical values. So what this means is that designs are not value neutral by any means. You have to make trade-off decisions informed by value systems. And all too often when engineers work together these what we call covering values for your trade-off decisions are unstated and unexposed for a rational reflection by the team themselves. So what the Dutch engineers have said was, very plausibly in my opinion, that you have to identify the value judgments that are motivating these various engineering alternatives. You have to also discuss openly how trade-off decisions are to be made. So part of this task will be also to use ethical value considerations to help guide your trade-off decisions like what does safety mean? What does our commitment to efficiency actually amount to? Now one more insight that I wanna draw out from the Dutch is that designs themselves, they mediate people's behaviors and expectations. Designs themselves that can be ethical or unethical in ways that influence people's behavior. This may sound a little bit strange when I stated in this abstract way, but we can think of plenty of examples in real life. You know that the design of workspaces, the design of people's workspaces will mediate how they interact with one another. The way you design a prison like the Pan-Optagon proposed by Jeremy Bentham will also be criticized by some as being unethical in how it influences behavior and how people interact in good ways or bad ways with one another. The way you design a coffee cup to go will mediate or encourage people to take it out on the road. Or if it's not a chigo cup, if it's a ceramic mug, sit down and have a chat over coffee. Take your time if they do in Europe, not like in America, like Starbucks, right? So we know from experience in everyday life, the designs really do mediate people's behaviors and there are good designs and bad designs that make people do good things or bad things on an unconscious level. You might even say that laws and policies are things that are designed by people and clearly people criticize laws and policies for being ethical or unethical. So this is not an unusual idea. I think we recognize this if you just simply reflect on our own experiences. So let me give you some concrete examples of how this collaborative ethics may come into play. Those of you who joined us for ethical frontiers in biotechnology last month with Jing Ping Fu should know that this is the paper that we discussed in very detail from his lab at the University of Michigan. So what they did here was a microfluidic system where you can feed into the bottom of those channels their human pluripotent stem cells that are then in this microfluidic system coaxed over just four days to form what would be essentially day 10 of human embryo development for study. Now, maybe we'll look at this kind of experiment and they'll say, you've created a type of M cell, a type of multi-cell or engineered living system that could be quite frightening for some people. So there has to be some understanding of what was the design choices that went into why it looks this way and how it operates and were there any ethical reflections along the way in informing how this M cell was created and designed. And happily the answer is yes, there's been quite a bit of ethical reflection. In my collaborations with the food lab, we have talked about making sure that these M cells or these embryo models, this particular type of M cell, are actually not complete in the sense that they have all the cell types and cell lineages that are represented in an actual 10-day-old embryo and therefore are not capable of full human life. So this was actually put into their ethics statement in the methods of their paper that I just showed you the title of. At these sacs, they lacked primitive endo germ. They lacked trophoblasts. They lacked various parts of a real embryo that would make it capable of creating a pregnancy. Right now, there were trade-off decisions along the way. They could have added all the components and tried to make it 100% as complete and accurate as possible. But they very clearly, very wisely, I think, chose not to make trade-off decisions in that structure and really balance it out in terms of other ethical considerations that were at play. So their design choices were informed by ethical deliberation and collaboration. So I'm going to pause here and turn it back over to Roger before I talk about moving this field socially forward in a responsible way. So let me stop this and go ahead, Roger. Why don't you share your slides? Okay. Let's see, can you see my slides? Not yet. Not yet. Okay, I don't see now the option to share all of a sudden. I think I need to get out of the show. There we are. Okay. There, how's that? Yes, we got it. Okay. So I started talking about a couple of these examples. I want to go back now to the motor unit on a chip. I remember I was talking about the fact that what we're really reproducing here is sort of the spinal cord with these motor neurons extending out these neurites that interpenetrate into the muscle over here, shown in red. And we're now starting to recapitulate some important organ functions in the body. And these cells, by the way, we've engineered so that they're, they express something called channel adopsin. It's a light-activated ion channel that allows us to activate the neuron simply by shining light on them. Those that activate a signal that gets transmitted through the neurites into the muscle producing a muscle contraction. Now, this is something that recapitulates just human physiology, but we can use that now to start looking at disease processes because we can develop functional measures. If you remember, I mentioned that the muscle was mounted or grown on these two posts. The posts are flexible so that the deflection of the posts can be used as a measure or a way to measure what the force of contraction is. And you can see here from the movie, the small contractions, the small deformations of the posts on each contraction. Now, with this model, we generated these entirely from pluripotent cells. So what if we go back now, if we're interested in modeling disease, we can take, for example, that are neurons that are generated from a healthy subject and also generate the same type of model from a subject that has, it's called sporadic ALS. In other words, there's no known genetic malfunction or mutation in these cells, except that once we tested and we found out that there was one that is common to a lot of ALS patients. But here immediately you can see in the structures that are formed, that with the healthy motor unit, these neurites extend into the muscle and they branch within the muscle and they connect up and they form synapses with the individual myotubes in the muscle. And with this, you can form normal muscle contractions. With the ALS motor neurons, though, what you find is that they can still send out neurites and neurites link up with the muscle, but it's much more random in pattern. So you can immediately see, just visually, the difference between the two, after, this is now after 14 days of co-culture. So we went one step further and said, well, could we use this as a model for drug screening? So we took, we looked in the literature and found two drugs, basudinib and rapamycin that are currently being tested, either in a phase one or a phase two clinical trial for ALS treatment. They both affect the autophagy in the cells. So we first of all looked at our functional measures. We measured the muscle contraction force. If you look over on day 14, this is the healthy motor unit, this is the ALS motor unit. And then when you applied either of the two treatments, either singly or in combination, we found that we've got some partial recovery of the muscle contractile force, demonstrating that we could actually see a difference due to the drugs and also a fairly substantial difference between the healthy and the diseased motor unit. We could also look, for example, at cell death. And interestingly here, even though the muscle cells were the same in the two experiments, when you look at muscle cell death within the muscle, you find that it's very low in the healthy motor unit, quite high in the ALS case. But then when we start to treat with either of the two drugs, again, we found that the amount of cell death that we observed, again, after 14 days, was significantly reduced. So we're doing here, it's just one example. There are a lot of others that I could have given, but one example of how you can use these M cells or these, in this case, microphysiological systems as a beneficial way of screening for drugs, for patients either with different mutations, for example, corresponding to different diseases. So obviously there are a lot of benefits that one can reap from using these systems. There are other systems that are being developed that at this point, I think it's fair to say they're mostly test beds for understanding the concepts of emergence and how to develop these M cells. These are walking biobots, these are biological robots where the muscle cells are seated onto a, in this case, a flexible substrate. And the muscle cells, they coalesce around this so that they can actually generate a contractile force. And the substrate is made in such a way that it's asymmetric so that as the muscle contracts, and here these muscle cells have been made optogenetic, so every time the light flashes, the muscles contract. They start to move along on the floor here. This is all in medium, and these are, there's obviously no real application for this at this stage, but you can imagine taking this step a step further and starting to make robots that could either swim or maybe invade into the tissues of the body and deliver drugs in a certain location. So this work has been going on at the University of Illinois, Urbana-Champaign with some of our collaborators from UNIX. Another of the studies that have been done, in this case by Mike Levin's lab at Tufts University is to design a walking biobot, but to do it through an evolutionary algorithm. And basically what he did is he takes cells from a frog embryo and he engineers some so that they're contractile, I'm sorry, and some that are not. And he looks to evolutionary algorithm, he can combine these in various ways and form different structures and look for designs that wind up being motile. So he generates a design, he can test it computationally, and then once he identifies a design that works, that can move around, which can actually meet the design criteria, he can then go in and he can make these from the frog embryo cells that he's engineered. And here's one example of the structures that he's generated. This is now a little, it's like a stool that has four legs. And these stools in this particular case due to the random contractile forces that are generated within the, this little contraption, whoops. He can generate the system that can again walk around and he can now optimize the system through his algorithm. Mike has been doing a lot of other interesting work looking at other cell types when they combine, conform, utility, even independently without any external intervention. So there's some really interesting work going on there. I wanna give you one more example. And this is an example from Ron Weiss' lab at MIT to generate a 3D liver organoid. And here what he's doing is, one of the main limitations of these organoids is the fact that they grow to a certain size. And here you can see some that have grown up to really a centimeter size, but there's a natural limitation to how large they can grow. And also a limitation to their functionality if they don't have the capability of being vascularized. So for example, liver can't really serve its function unless it has a vascular network going through it. So what Ron has done in his lab is that he's engineered some of these cells. So that if when he introduces gata six into the cells and he can then turn on the gata six at some point in time during the differentiation process during the growth of these organoids and whether they have high gata six or low gata six that determines whether they go into either mesoendoderm or ectoderm and the cells that go into the mesoendoderm path can ultimately form into the liver like what you see on the right-hand side there. The ones that go into ectoderm can ultimately form into a brain. So we're starting to gain some ability to control the structure of the organoids and being able to do this even in a temporal manner and turn on certain signaling pathways at a certain point in time. So these liver organoids, the ones that he's induced to actually form vasculature look something like this inside and the green, you can see it looks like a network structure. The green actually has a marker for endothelial cells. And let's see, there we go. And you can see the networks that are forming. And one of the things that Ron and I are starting to work on together is being able to connect that internal vasculature with an external vasculature that we can then perfuse. One of the methods that we're using to do that is to generate, in this case, we're using a brain organoid. So we use one of the microfluidic systems of the type that I was showing you before. Here's that central region that I was showing you and here's a, this would be a brain organoid. And the green lines around the outside are meant to represent vasculative structures that we can grow. Now, we've actually started doing this. You can see here, the green vasculine networks around the outside of here, the brain organoid is expressing a red fluorophore. And the fact that the blue that's inside the vasculine network shows where the network is being perfused. And at this point in time, we can get some of these vascular structures to start to grow into the brain, but you can see that we can't quite perfuse it. But we're getting very close. And I think we're within probably several months now, both our lab and other labs around the US and the world where we will be able to vascularize these organoids. We will be able to grow them to larger structures. And with a vascular structure and perfusable vasculature inside, we'll be able to control these systems much more finely and accurately than we can today. So it raises the prospect that we could now, probably within a relatively short period of time, have brain organoids that are perfused. And as they're perfused, they can grow to larger structures. We can start to communicate with them. And it raises all sorts of interesting possibilities, but also a lot of interesting questions. And I just want to end by mentioning what some of those questions are that maybe we can discuss in the discussion period later. But you start to ask, at what level of complexity does a biological machine become a living organism? And what actually constitutes life in an M cells? Is it the ability to self-repair itself? Certainly these things can already self-repair to some extent. Can they learn? Some of the systems, for example, that Mike Levin's been working on actually showed that these systems can learn and have even a non-neuro memory. They can adapt to the changes in their environment. And some of the systems are even getting to the point where you might ask whether they're actually replicating themselves. I just want to end by saying that these are some of the issues, types of issues that we've talked about in our NSF center at ebics.net. They're ethics modules that we've generated and where we've discussed some of these ethical issues within the center among the students and faculty and postdocs. And if any of you are interested, you'd be welcome to go to this website and see what we have to say. So at this point, I will turn things back to Insu. Okay, thank you, Roger. So let me just take us down the home stretch here before our Q&A session. And point your attention to a recent publication that came out of a series of NSF funded workshops around M-cells involving the M-cells research community. And here we really focus on trying to articulate what it would mean to build a community around responsible research on this type of biological emergence that we spoke of. I'm going to go through the details on this. I just want to give you a few highlights of this article. One of them is that we have to acknowledge that M-cells research is not just about pursuing abstract scientific knowledge. It's also about creating a technology that's going to have specific societal applications. This is where the engineering ethics comes in in the bioengineering ethics discipline I'm trying to build. Now, some of the questions that emerge about M-cells has to do with selecting and developing those kinds of societal applications in a way that A, the potential benefits are going to be fairly distributed and B, the creations themselves or the knowledge gained through their use does not lead to some biosecurity risks or malevolent uses. For example, maybe some biosecurity risks or malevolent uses of biobrobots. Now, just to give you an example of how specific societal applications will really drive the future of many of these M-cell technologies. I'm just giving you one salient example now. Roger had mentioned organoids, right? That's a very important M-cell type. And an organoid, for example, a lung organoid can be developed through stem cells to mimic the basic organ structure of the lung. Now, lung organoids are going to be used for many studies that try to develop and study interventions for the COVID-19 virus, right? Because you can't study in an animal lung exactly what may be going on in a human lung and you can't study patients themselves in an easily accessible manner as you could with an organoid. So here we have an M-cell that could be vastly important for the development of a societal application, namely strategies to combat coronaviruses. And so, you know, this presents an enormous opportunity but then there raises the questions of how these benefits that flow out of this type of research should be fairly distributed around in society from, for example, the drugs you might develop through this platform. So we really do need to think about preparing the next generation of researchers, the next generation of researchers, for example, that go through Roger's lab and are trained by Roger and his colleagues in order to help them get ready for what we want, which is collaborative scientific, ethical and societal deliberation through this co-culture of ethics and science that I had mentioned earlier. So how should we facilitate that kind of inclusive deliberation, not only amongst the co-culture, you know, community of the ethicist and the scientist and the engineer, but also with the public and other interested parties that have some kind of a stake in M-cells research. So let me just finish with my last main graphic and there are three different ways to answer the question. How do we bring different points of view and deliberation into the mix? I'm gonna use an analogy that may be familiar for drivers in the United States. Okay, imagine that you have three lanes on a highway, all heading toward the advancement of a biotechnology of three approaches to doing this. You know, you can either be in the fast lane, which is gonna be basically based on assessing risk and efficacy. And think here of the sort of orientation that the FDA takes for technology development, right? You have a source of uncertainty and that source of uncertainty is just the lack of data. We don't know if this drug or we don't know if this biologic will do what it's promised to do. So how do you base your decision-making? You gather more data, you do more experiments. So with more data comes less uncertainty. And what is your policy approach for the go or no go decision for deployment into society of this technology is gonna be based on risk calculation, right? So that's essentially what the FDA is focused on. Now, this is the fast lane, even though you may think the FDA doesn't move fast enough, this is the fast lane for advancing a technology. There's also a middle lane, though. And actually as a driver in the US, I actually prefer riding in the middle lane for personal reasons, but the middle lane is one where you have uncertainty. It's always present, right? Sort of like an ineligible part of new technologies. However, how do you base your decision of reducing uncertainty? You have to use diverse methods. You have to use diverse stakeholder viewpoints, including ethicists and engineers. So this is the sort of the collaborative approach that we're gonna talk about. And the policy approach for the go or no go will be based on knowledge that's not simply just risk benefit analysis, but a more diverse set of considerations that might include sociological, social justice considerations, access considerations, things like that. So it's much more pluralistic. And then you have the slow lane. Now you definitely know people in the slow lane here because they can't wait to get off a highway. They're looking for the nearest exit off that road, right? So what do people say here? They're gonna be the pessimists. So the people in the fast lane are the technological optimists, the people in the slow lane are the pessimists. I'll say the source of uncertainty here is just the inherent capacity for these new technologies to cause harm. They're all gonna be in some way harmful. How do we go with the go or no go decision? What is the basis for decision-making for deployment? It will be controllability. For example, can we control gene drive? If we unleash this in the environment, those of you who know what gene drives are, I will know what I'm speaking about here but I haven't explained what that is. And then the go or no go decision for policy will be based on technology selection. So people might say things like this, right? In vitro fertilization, yeah, poses some inherent risks and harms for people. It could be difficult to control how people use this technology. So you know what? Let's get off this highway and let's just encourage adoption. Let's encourage another form or another road to get people to the goal of let's say having healthy children that they can love and raise, right? So technology selection. Let's not go with gene drive. Let's put our efforts toward medicated mosquito nets and the deployment of these or to try to do a better job of dealing with standing water in communities, right? Technology selection. I think that for MCEL to proceed, I would recommend the middle lane. So don't look for off ramps and say, we don't need organoids, we don't need embryo models, we don't need the kinds of biorobots that Roger had alluded to. But we need more people involved in the mix and to base our decisions on a more diverse set of knowledge. So I'm gonna just end with this last quote in the paper that I alluded to earlier that was published in Biofabrication. What we say here amongst the people who participated in this NSF workshop is that MSOLs, they actually have the researchers, they actually have an opportunity here. They have an opportunity to proactively lead a robust ethical conversation, one that goes beyond just the requirements of standard ethical regulations. It goes beyond conventional wisdom that the public should be just simply educated and consulted, but they're actually not co-culturing the development of the field. We as the authors maintain that the commitments and the strategies that we propose in our paper if adopted could help fulfill the potential to establish MSOLs as an ethically responsible community and actually as a model for future emerging technoscientific fields. So with that, I would really love to hear the questions that you have and we have half an hour that Roger and I would be happy to field the questions for you. I thank you for joining us in the formal part of the presentation. That's for contact information if you wanna follow up in any way. If you wanna email me, I'm happy to send you PDFs of both articles that I had mentioned, both the SELS MSOL paper that I had written a while back about engineering ethics and then the other group paper that I mentioned from the MSOLs community that was published about fabrication. So I'm happy to send you these papers if you wanna take a look for yourself and let's turn it over to Q and A. So I'm gonna stop my slides here and let's go. Let's hear what you have to say. So I'm gonna rely on our helpers here to read off the questions for us and that's how we'll run the Q and A session. Go ahead. Hi everyone. So thank you and to Roger for your collaborative talk and showing us how co-culture would work between various stakeholders like scientists, engineers, ethicists and policymakers. While you all take a few moments to type in your questions in the chat box to either Sarah or I, you'll see us with the co-host label. Sarah has a question to start us off. Yeah, so just to begin, the creation of MSOLs raises the question that's common in synthetic biology, emergent behavior and living systems on whether or not you're creating life and Dr. Kim, you touched on that briefly in your presentation as well. So I'd just like to ask in your opinion, are you creating life or are you merely just rearranging it or how would you even start to address that question? That's a great question. I guess I could start with that. My own feeling is that we are creating new forms of life, I guess. But we're doing that by taking pieces of existing living systems, existing cells, modifying them in some way and then reassembling them. So it's not that we're creating life so much but that we're creating new life forms in a sense. And I think as we progress through our research, those constructs that we generate are gonna become more and more complex and they're gonna have greater capabilities. And I think it's, I think the question really comes down to at what level of complexity or what level of capability do we ultimately say, well, this now has not stepped over a barrier but moved into a new realm where maybe it needs more stringing constraints or considerations. And Sue, do you wanna comment on that as well? Yeah, sure. Yeah, this is an easy question. No, I'm just kidding. It's a very difficult question. So the short answer to the question is, in one sense, yes, we are creating life because it's actually in the term itself, M cells, engineer multicellular engineering living systems. And there's a sense in which the cells that we use or not we but people like Roger use to make M cells, they are living cells, right? Cells can die. Your M cell can actually die if you don't culture it properly to people's dismay in the lab. So there is a sense in which they are alive in a cellular sense. But then the deeper question I think behind the question that was posed is, what do we mean by kind of a morally significant life? And that's the harder one, right? What do we mean by morally significant life? If anybody looks up definitions that people have proposed or what an organism is, so not like a single cell, like a neuron, like a neuron could be a live or dead but actually an organism. We don't call these M cells organisms, call them living systems, right? What is involved in something being an organism? Well, maybe it has to have certain key features that M cells simply lack at this point. Maybe you might build into your definition of an organism as how the capability of reproduction. It has to have the capability of adaptation or learning. Now, these are high level abilities that I think at this point, Roger, correct me if I'm wrong, but I don't think M cells are nearly at that level yet. So I think that that is a very interesting question. I think that the better way to frame it is to ask at what point are we creating an organism and furthermore, are we creating an organism for which we owe some level of moral respect? People create M cells, I suppose, in the lab all the time in the sense that you might make a transgenic mouse. You have a transgenic mouse that doesn't exist in nature. It's not a natural kind in the fullest sense, but clearly it's alive. It's able to reproduce, it's able to adapt, but people don't think that that is wrong. Maybe it's simple because it's non-human. So obviously if you made a synthetic embryo or embryo model that could be capable of making full human life, people might say you're actually making life there in the moral sense. So it's a rich question. It's a difficult question to answer because to even ask the question, you have to make some value presuppositions that people may or may not share as kind of a background assumption to that question. So thank you for that question. Is it a good, tough one to start us off with? What are some other questions? Okay, next we have from Angela Alberti of Harvard Medical School. To either of you, how is ownership or the patenting process of these technologies being determined? If these systems are able to create much needed organs, who gets to own these techniques and should one entity be allowed to own them? Ooh, another good one. I'm gonna send it over to Roger because Roger, when you make M cells, you must obviously have to deal with this question about who owns this thing, right? Because you use donors. Absolutely. Yeah, so please give us your experience. Yeah, so for example, I mean the model that we have of the motor unit is something that we submitted, we prepared and submitted a patent application for. So it's a living system, but it's a, I guess the patent is more on the device that we use to generate the system inside, the procedures that we use in order to generate the, first of all, differentiate the different cell types and then get them to interact with one another. So maybe it's not that we're actually patenting the organism or the living system itself, but more the process to make it. I think as the systems become more complex, I think the kinds of questions you're asking probably gonna become more and more difficult to answer. But right now I'd say that by and large, these systems are being handled in a fairly routine way and dealt with as any kind of an abiotic invention would be. Yeah, Angela, that was a fantastic question as well. And let me also give you a bioethicist response. Actually much further up in the causal chain of MSUL's research. So IPS cells are cells that you create by taking a patient somatic cell sample, like skin cells or cells that you might find in peripheral blood. And you reprogram and allow it to take on stem cell like properties of like, let's say, a human embryonic stem cell that can create all kinds of different cell types. And this is like the building block of MSUL's, human MSUL's, right? Who owns those IPS cells? Already it's been pretty well established internationally that it's gonna be the research team that's derived the IPS cells from your skin sample, for example, right? So your skin sample has your genetics and so does that IPS cell line. But that question of who owns that thing has already been settled at the very first step of IPS cell derivation. And then when people further improve upon nature by mixing their labor with them, I'm gonna echo John Locke here. If you mix your labor with some raw material, make it better, so skin cell to stem cell, then it becomes morally, according to this view, yours. It becomes your property. Now imagine taking IPS cells and making them even more complicated and bioengineered down the road to something like an M cell, okay? So kind of in the moral, political, philosophical response to the question, I think that question has really been settled in a controversial way because not everybody agrees with this. Way, way, way back when the donor provided cells to a research team to make IPS cells, right? So I can't imagine that down that chain of development, we're gonna suddenly roll all that back and give ownership back to the original cell donor, even though there are some people who would argue that that original cell donor has some kind of reach through rights to the use and direction of how their cell line is manipulated by other researchers. And some might even argue that they have a reach through right for royalties on commercial value. But that's a minority view, I think, in bioethics, although a very, very compelling, interesting one to contemplate. But that question of owners, by what I've been saying, it's kind of been quote-unquote settled, at least in the US courts, way back in IPS cell derivation, which are the building blocks for M cells. Okay, great. There are no other comments about that question. I'll start with the next one. So regarding ethics, should there be limits on the extent to which bio machines are engineered so that the organism does not stand up and demand that it has legal rights or the right to vote? Should vocal organoids be developed and engineered so it speaks independently without any language programming at the level of a third grader? Okay, well, to be fair, I'll jump on that one first. So that's a good question. People who attended an earlier ethical frontiers talk that I did with George Church should recall what I said back then about the concept of minimal personhood. So let me revive that concept for you here now. So the question seems to really push on the possibility that we could get to a point with some of these more complex multicellular systems to have at least maybe not the MSL speaking up for itself but like the question proposed, but maybe people speaking on behalf of the MSL's interest to say, is there something here now that deserves our moral forbearance and respect in the way that you would also grant that to an organism that had some capacity for moral status, whether it's sentience or the ability to feel pain or the ability to communicate or interact with this environment, right? So I propose that a good way maybe to think about the limits of MSL's research or other kinds of bioengineering systems research is to ask hypothetically, is there a concept of minimal personhood that could be useful here? By minimal personhood, we might mean something like philosophically, what are absolutely the minimal standards that need to be present for something in the dish to be considered a person in the moral sense? I don't mean like a human being, but a person in the moral sense or even the legal sense. A quite a lot has to probably happen to get to that point. Now, I'm not gonna belabor like what I said back in, I think it was December in that ethical frontiers lecture, but here's where the collaborative design and ethics comes into play, what I call bioengineering ethics because if we had an idea of where that threshold was where we would really start to question whether or not you've created some kind of artificial person. And by the way, this comes up in artificial intelligence and it can come up with non-living matter engineering, like computer engineering, okay? So we're not just talking about MSL's here, but if you have an idea of where that threshold is just above or we're kind of getting to that point where we're wondering, is there, what's in the dish? What is that? Is that a person? Is that something with the rights? If we hadn't agreed upon an idea of where that was, that would be very useful for research teams than to know where to back up. Like you're getting into the red zone and you're getting up to that level. So I think there's kind of some interesting work ahead of us where we could talk with both engineers, bioengineer, scientists and philosophers to kind of deliberate about in the real world of the lab, where would that line be? And how would we know that we're approaching it? And just to kind of like think this through in advance, it's almost like, you know, not quite pandemic planning but something kind of like that, you know, something to kind of get ready and know where the line is. And then just back off it or just don't get up to that point. So I think really what the question is asking is at what point does an MSL become a person that have rights? And that's something worth thinking about in advance and we need this collaborative effort to kind of define the boundaries of the research and just ensure that we don't flirt too close to that line but still leave plenty of room for innovation and biotechnology growth and benefit for society. So I hope I've done something to address that question. Roger, I don't know if you wanna add anything to that. Yeah, just kind of a different aspect of the question. It was asked in the context of, you know, could this living system at some point verbalize and express itself? And I don't think you have to go that far or to be a, you know, a living system because we have ways of interrogating these organoids. We can introduce signals to it. We can look at the way it's responding. We can get feedback from it. So in a sense, that system is already communicating with us. It's responding in some way that we can at some level understand. And it doesn't have to be verbally. It can be through a certain pattern of neurons being activated or a certain growth pattern or some kind of feedback that we can get. And I think as we, I think probably in the much nearer term will be a situation where we can start to develop these organoids and probably the brain is the best example. But then we can start to communicate with it. We can stimulate it in certain ways and we can then observe through a number of different sensing mechanisms, we can observe its response to our stimulus. And that's, even at that point, I think the question becomes relevant. Yeah, I was informed that we have a lot of questions pouring in. So we're gonna have to try to keep our answers much shorter. I would love to just be able to have a fireside chat and just share a viewer with everybody and just talk about this for hours. But we don't have that kind of time. So let's cycle through these a little bit faster. We'll try to keep our responses brief is still, I hope, fulfilling in some way. So let's go with the next question. Okay, an audience member asks, would it be wrong to consider this technology as a sort of prosthetic device instead of a living mechanism? Interesting. Rosha, what do you think? I mean, yeah. Well, they certainly could become prosthetic devices. I can imagine a living system being developed in order to assist somebody who has some disabilities. But they wouldn't necessarily all have to be that, at least in my mind. Roger, can you just touch on what once in conversation you and I talked about hyper organs or like hyper organ noise or something like that. I mean, that might be a kind of prosthetic, right? And it kind of gets in that direction. Yeah, so hyper organ would be an organ that maybe performs the same function that say a liver or kidney does, but does it more efficiently or maybe a heart patch that can more effectively pump than our current muscle cells. So I think that those are assist devices. And there's certainly, hyper organs is a nice term that we've been using to describe these systems, but that's an interesting application. Yeah, yes. I would say it's actually not an either or. You could actually have somebody that has an MSL and a prosthetic. Yeah, absolutely. Okay, next question. Okay, great. So the next question is, how is research of MSLs in the private sector different from research of MSLs in academia? How can we ensure that this discussion of bioethics is maintained in both academia and the private sector? That's a great question. Roger, what are the differences in the two spheres? Gee, that is a tough question. We do a lot of work with, you know, pharma or biotech companies. And I don't see many differences between the way in which we address these questions. In fact, some of the people that we've engaged in conversations are people from, you know, companies in the local biotech industry. And they have much the same views. And I think the same responses to questions like that that we do. Yeah, yeah. And I would just briefly add to that that I have done some work with, you know, biotech companies around ethics. And I think we need to be a little bit careful of not casting it as sort of like a dichotomy between academic research that's going to be kind of a little bit more ethically tuned and responsive. And then sort of like, you know, evil private industry. I think that there are plenty of people in industry who are very, very sensitive to ethical issues. And in fact, it's a good business model to sort of make sure that your practices and the products you deliver are developed in an ethical manner because if people find out that something went badly, ethically in the course of research is not going to look good for the product that you want to sell later. So I also kind of want to push a little bit back on the assumption of maybe academic research is a little bit ethically cleaner than industry. Good question. Next question. Okay. Oh, you got it, Linda. Yes, I do. I'm sorry for that. Okay. So an audience member says that unsells development will likely have a significant impact on the number and nature of procedures to which sentient animals and laboratories will be subject in future decades. Do these lab animals deserve to be considered stakeholders in this developmental process from Zeke Benchurin of Harvard Medical School? Okay. Well, that's a question I'm sure many people have on their minds because animal research is a highly sensitive issue for a good reason. My answer to that is actually that I know of many M-cells researchers who want to be able to offer their M-cells platforms as an alternative to animal research. So if done well, and if it actually does recapitulate some human organ systems, let's say, you know, organoids, for example, will be one approach. Then you have an experimental system that's all human and could be highly controllable, scalable. You can do a lot of drug screening on your organoids, which if you design them in the right way are not going to have human rights or they're not going to be so complex that you start to wonder whether you've created an organism. But you definitely have a little miniature organ model. I always suspect that actually the advancement of this field will help ease the need for animal research. Roger, what do you think? That's exactly what I was going to say. I think if anything, it'll lead to a reduction in animal experiments. And I think that's, in some respects, the motivation that a lot of us have that we would like to see a reduction in animal use and drug screening. And this is a good way to do it. Right, so if you imagine that metal lane that I pointed out and you have many different people weighing in on the co-culture of the ethics of this field, you can imagine there's a space there for people who are very concerned about animal use and research. I would imagine that they'd be very important collaborator in moving the field forward. Next question. Okay, great. So we may have commented on this a bit, but I'll just read the question. It seems like personhood is most closely connected to subjective experience, which is emergent from advanced nervous systems. Is the concept of being alive over-emphasized with respect to moral status? So, good question. So yeah, whoever asks that is correct. I mean, personhood is really kind of more associated with these complex capabilities that you're not gonna see in M cells. And maybe we're being a little bit confused by focusing too much on the human cell aspect of these things. I think I tend to agree with what the person said. I mean, that's why I don't really worry much about personhood emerging. It's one of the emergent things that could happen because we mean something so much richer than like biological organization. The one thing I will point out that is an area for further debate philosophically is that whether something could enter into the status of personhood, simply on the basis of having the future potential to have these more complex capabilities. So that's what people say about embryos in the dish in a fertility clinic. These things don't have any of the biological substrates yet for consciousness. They'll say they have the ability in the bright conditions and the potential to do so. So that potentiality argument, if it works there for the human embryo that's not yet fully formed, might be applied for M cells if somebody believes that under the right conditions that M cells could further emerge and develop into something much more complicated. So I think that the potentiality argument is actually something that could be a factor here though. That's also something I personally actually am enamored with. I'm not all about convinced philosophically with the potentiality argument for personhood. I think there are some mistakes being made there philosophically, but I can imagine people definitely applying that potentiality argument to M cells. So I don't want to cast that aside completely, but yeah, I think that we're far away from that right now with M cells project. Yeah, I agree that I think that's quite a bit off in the future, and these are things that we need to discuss earlier rather than later. When we've actually formed in M cells that has a personality, has certain features and characteristics, I think now is the time for us to have a discussion. So I think it's a good question. Thank you. I think we have time for a couple more questions. Here's another question by anonymous. How accessible would this technology be for developing nations? Are there any concerns regarding medical access and economic gaps among nations? Related to this is the second question that are we only focusing on quote unquote western diseases with this technology? Yeah. Yeah, if I ask the question in tonight's session as an audience member, that would be the question I would ask. If I want to say so myself. So this is a topic that actually I talked with Roger in the past and his colleagues at MIT. And the challenge I posed was imagine this collaborative ethical approach between the ethicists, engineers, you might have other people involved, you know, citizens. And the challenge is this, right? We can make M cells do many different things. There's the whole engineering aspect of it. You can design M cells in many different ways and only constrained by the actual biological properties and constraints of nature itself. But aside from that, so many things are wide open. This is an engineering goal, because remember engineering always has some kind of goals to meet. What if we say how can M cells improve the lives of people in resource-poor communities? How can we design from the very beginning an M cell that's going to be beneficial to people who are the worst off and who are the least advantaged? If that is going to be your solution space that you've sort of constructed under which now you're free to play and come up with better or worse solutions, I think that's an enormously useful and I think admirable goal to start off with. So I don't see anything incompatible with M cells research and exactly the kind of concerns that the anonymous questioner had just raised, because that I would want to probe and investigate and motivate M cells researchers to take in their design phase very early on. Roger, what do you think about this? Yeah, so I guess what you're saying is that it really depends on what the motivation is of the researcher. And whether that motivation is to develop technologies for the developing world or is it for developing technologies that can hyper-organs, for example, where somebody could develop a retinal implant that can see in the infrared and that this would only be, I mean it doesn't cure any disease, but it is sort of an enhancement that somebody, if they had enough money, they could have that surgery and they could have that capability. So two very different approaches and I think it really depends on what your end target is as to which, you know, whether it's going to be beneficial to the developing world and to those less fortunate or whether it's only going to be available to those that have the money and can afford it. Yeah, yeah, I remember sitting Roger with you and some of these M cell scientific meetings and we had presenters talk about like, you know, these biofilms that are multicellular that could be like used to detect toxins in an environment or in water. So you can imagine it is kind of enormous public market, you know, but you can imagine it is a lot of uses in resource poor countries. If you can make it available and scalable and affordable for people to deploy in those contexts, right? So engineers, you know, let your imaginations run free through a social justice framework and I think you might have some really interesting solutions for some of these problems. I believe we are going to end this last minute of thanking everybody for joining us on ethical frontiers. We're going to have our next event May 7th 5pm and that will be on the issue of brain organoids with Paula Arlada from Harvard University. She and I will talk us through more specifically ethical issues that are raised. One very exciting type of M cell, which are brain organoids. So please join us for that. Look for that advertisement and they'll be through Zoom just like this. And I hope you enjoyed it today. I really enjoyed presenting my ideas for you and Roger, would you like to say anything? Yeah, I just would like to thank the audience. I mean, it's a little strange presenting this way, but I thought the questions that came up were great. A lot of the same questions that I would be asking. So I very much enjoyed it and thanks for everybody's attention and attendance. Okay, well thank you everybody. Thank you Sarah and Linda for feeling those questions. There are my graduate students at Harvard Medical School and I'm so proud of the work that they've been putting into this and to the program itself. So I'm going to say good night from here and I hope to see you all or not actually see you, but maybe speak with you over Zoom on May 7th. Okay, have a good night everybody. Thank you.