Please note that our audio conversation with Manu has been lightly edited.

Manu, 00:00 – Science doesn’t happen in some fancy labs in some big universities like mine. Science happens on kitchen tables and in school rooms and anywhere and everywhere we look, but we just need to empower everybody to have the kinds of tools to be able to make observations, I think. But now the question is how do you do that?

Erik, 00:28 – Today’s guest is Manu Prakash, a physical biologist, inventor and associate professor of bioengineering at Stanford University. Manu was awarded the MacArthur Fellowship in 2016 and has received numerous other prestigious awards. His research is driven by curiosity, empathy for solving challenges in underserved communities and a passion for democratizing access to science.

Sachin, 00:52 – In this episode, we cover his philosophy around curiosity-driven science and the power of observation, trends in bioengineering, the water-droplet computer, and the anti-gravity machine, which answers questions about life in the ocean. We also discuss the idea behind frugal science and his Foldscope and Paperfuge inventions and why democratizing access to science is a global imperative.

Erik, 01:32 – Let’s maybe start at the, I guess, root of everything – where you were born, how you grew up, and then eventually your path into academia.

Manu, 01:40 Yeah. I grew up in India. I’m now a faculty at Stanford and the route just like everybody else I guess is quite chaotic in some sense. I was born in a town in UP India, northern parts of India, called Mowana, which is a sort of small town by any means. My mother was an academic; she taught political science all her life and I took the classic route of Indian parents telling their kids, “are you going to be an engineer or a doctor?” kind of a strategy. I almost went into the Indian Air Force, but my dad sort-of kind-of vetoed that out. And so I, you know, I went to the classic IIT style structure and I think from that I went to graduate school at MIT and then I was three years at Harvard before starting at Stanford. And I think, yeah, maybe I’ll let you guys explore depending on how much detail you want to get into. But an interesting anecdote – none of this was obvious and it was not clear every step of the way what I wanted to do, which is, I think, very typical for most people in academia. But what’s interesting is at least there was a very dramatic switch that I’ve made in my life all along. My undergraduate degree is in computer science; I told myself I’m never going to just sit in front of a computer all day. I just don’t want to do that. And it was a much more of a personal choice. And then I did a PhD in applied physics and then was the big transition to biology personally for me and that’s been a big part now for me. So it’s, you know, I think some of these transitions have been quite valuable just personally for me.

Sachin,  03:58 – Why does research and academia resonate with you? Did you actually consider some other professional paths?

Manu, 04:04 – You know, now, when I think about it, this is just very clear what I wanted to do and I am looking for places where I can execute and make that happen. And some of that is structured on what I just truly call curiosity-driven science because that’s the one theme that unites my lab and what we are trying to do. And on the other hand there are very specific themes in which we are trying to structure, at least making science much more accessible to people than I can imagine that can also be done in many different ways and forms. Yeah, I think it’s just… I like the freedom of waking up in the morning and just, if there is an idea that you’re truly excited about, I think, you know, other than the fact that I eventually have to pay for it somehow, there are no true barriers. It’s something that I deeply care about to be able to explore. And then, there are other barriers associated when we try scaling up ideas that require different kinds of infrastructure, different kinds of capabilities, but still we explore sets of things and actually sometimes not being driven by what the market and the rest of the world is gearing towards is a good thing. So, many times when I’m thinking about ideas, I sometimes don’t want to be dictated by what is currently possible or what is needed. You could, yeah, there is a sense of isolation that you can get, but then later on if you choose to, you can completely integrate yourself in the real world as well. I like that.

Sachin, 06:04 – When it comes to curiosity-driven science, you alluded to it. What do you mean by it? How did the genesis happen?

Manu, 06:13 – You know, there is a very pragmatic answer to it. I started my lab and I was excited about many different things and I made a conscious decision at the time to continue to do what drives me and gets me excited, which is, surprise. You know, this is why we do science. As a scientist, I thought, what is my superpower? Everybody seems to have superpowers, and I think the way I think about that is I think about observation as my own, just personal capacity. I really enjoy observing, but I also do see sometimes things where others might not see something. And, of course, there are times when I don’t see something but others do see something. But there was a very conscious decision that I made at the time of starting the lab what type of a scientific community do I want to grow and seed. And it was this notion of keeping a like-minded nature of what we are trying to do. And I was literally putting together a website for my lab, that could actually encompass what I wanted to do, and that’s when I sort of penned that down. There was a very conscious decision I made around that time as well. This is almost seven, eight years ago of spending a specific percentage of time in solving the problem of access to science. And that led to the frugal science part of our lab and much of the activities we do in there. That was a very conscious decision. It’s not an accident because eventually, I have to carve out my time in thinking about sets of problems. So to a certain extent that’s very pragmatic. But also on the other hand, it’s just who I grew up to be. You know, I’ve always been like that. I’m excited to learn just like you guys. And it’s something that… Our world is just such an incredibly wonderful place and sometimes in the most mundane things are hidden just incredible gems. And if you don’t take a holistic view sometimes on science, you are blinded to what you are looking for, not what’s there. And I think this is a huge problem in science that this type of a thing removes that kind of a blinder.

Sachin, 09:27 – You mentioned observation as one of your superpowers. Could you elaborate? Could you share some examples with us?

Manu, 09:35 – We all live our lives, and we’re all bound by the same laws of physics, same laws of chemistry. But there is many ways we can perceive this world and most of the time I find that the first time you look at something, there is a viewpoint that you’ve constructed. So you know, our perception of this world is pretty much constructed on what we believe is true or what you are seeing in the same phenomenon. You might be washing dishes and although it sounds like a really mundane activity, there’s an infinity of interesting things happening right in that sink at that very moment. There are many attitudes you can take while doing dishes, and one attitude to truly take is what remarkable number of phenomena are just occurring right in front of you. And if you really take that seriously, something that falls out of this very acute nature of… Here are 15 different things that are happening right in front of me that I truly cannot explain. And it’s not about, oh, somebody must have figured it out. It’s about whether you can make sense of it at that moment. The irony of this is our experiences are so determined by the length scale of our perception and our life. So when you zoom in, and even 10x zoom, and you watch the same sets of phenomena, now either spatially zoom in or temporarily stretched out, slow down time so you could watch things happening just a little bit slowly, we immediately realize we lose all intuition. And this is how I got started in biology, just trying to extend the intuition of… From human scale to cellular scale and it’s just been remarkable that every little thing that you observe at a smaller scale truly breaks intuition and you have to ask how does that work? So I think that’s what I meant by observations. I think there’s a beautiful essay – Tim Mitchison, a famous biologist who wrote… He calls it “Developing a Taste in Science”. And what I also mean by observations is, there are certain observations that you find fascinating while another set of observations you find mundane and you go to the next person and that description is completely different. So it’s partially about taste as well. I like the idea of finding a thing in physics – there is a classic term for it, which is called toy problems. Now, toy problems are just the right level of simplicity that you are still not diluting the sense of the problem, but you are throwing away the fluff and in biology that’s not commonly used or thought about. And I think in the last 10 years almost all problems that we’ve been working on in biology I could classify them as toy problems, just because they keep the essence of an idea that I’m thinking about. But they are the simplest possible form of those sets of questions and I think their observation is quite powerful because it comes from just making an observation, and it was easy enough to make the observation and then you still have a mammoth task of trying to figure out how that works.

Sachin, 12:44 – Yeah, and that’s very relevant. Translating the observation into the questions one may have and try to answer those questions. How does this observation phase in your experience translate to research and problem solving? What are the approaches you may be applying there?

Manu, 13:07 – I often think of observations as my little reservoir stock; it’s the raw material. Making an observation kind of makes you anxious for that short period of time because you can’t explain it, and to not wrestle with it too much and file it and still keep coming back at it over and over again is very useful because you might not make the connections with why is that problem actually deeply interesting immediately. So one example is we made an observation, we make observations collectively as well where there is a gut feeling that I have about, ah, this might be a fun system and multiple people in the lab are playing with it. And sometimes maybe we’ll just observe something under a microscope that’s a surprise, but it’s not really clear what that means. And you have to just let it simmer for some time. This is why you cannot shut down observations. You observe all the time. You don’t observe for relevance. It’s not like sorting, where I’m going to keep sorting until I find something, because of course you will never find something that exactly fits your framework of the sets of questions. So it’s much more of a parallel processing while for certain sets of things you’re making matches while for others sets of things, you’re just growing your power of being able to observe phenomena and be surprised by them. Turning things into questions is a whole other matter, and I think it’s very much driven by what types of questions we find exciting as individuals. I mean, one example of something like this is some work we’ve been doing for a while now where we made an observation that literally, quite literally anybody can make in their kitchen. So talking about kitchen science. You can take food coloring, and you can take a clean glass slide or any clean surface and you put food coloring on that, food coloring as in the same thing you use to make cakes and all the other good stuff in the kitchen. And you make a remarkable observation, which is the drops of food coloring seem to have a certain sense of agency, which is puzzling. So when you keep them by themselves, they are just jiggling to puzzle you. But then when you put two of them together, they can see each other, they can sense each other and they can crawl towards each other. Now that’s a real surprise because something like that as an agency of being able to detect and move and sense is something that we associate with biology. We associate the capacity of making local decisions in almost matter-like form with living things and then when you put lots of food coloring drops just sitting on a surface, you really observe extremely organic phenotypes of things chasing each other and breaking each other, but searching for each other, for example. The question that, I mean, of course we sat on this observation for some time, but the question that we connected this to was the idea of a very powerful idea in biology of this agency is associated with how do you sense your environment, how do you process it and how do you act on that. That can be distilled in truly an inanimate system and this ended up becoming the simplest implementation of an idea in biology, which is called chemotaxis. It started by just observing drops of water misbehaving quite literally, but it actually answered quite a profound question for us, which is it’s feasible to implement the complexity of chemotaxis in inanimate matter and to this date it’s the simplest example of chemotaxis. Looking at it, it’s not so simple. As a phenomena, it’s very easy to observe and then we spent four years trying to explain it, and that was fun because we just didn’t know what we were seeing. It really comes as a surprise. That’s what I mean by, when I make an observation versus when we truly have a question. Sometimes it takes time.

Erik, 17:45 – What is chemotaxis?

Manu, 17:47 – Yeah, chemotaxis is very simply that quite literally in your body right now there are millions of white blood cells rushing around looking for someone who has entered your body without you knowing, say a bacteria. Now the bacteria is possibly generating a signal because it’s leaking out certain molecules at a certain rate and this white blood cell can figure out where those molecules are coming, where its source is, and quite literally chase and run towards that source. And even while the bacteria is also running away, there is a police chase effectively and that’s happening literally in all of our bodies right now. And if that process breaks down, that’s the breakdown of the entire immune system. We would not exist too long if that process did not occur. I mean this is the simplest form of it, but it occurs in many, many different ways where there is an information gradient mostly in chemicals that is laid down in the environment and a single cell has the capacity to read that information gradient and act on it. It’s equal to having pizza in a building and and knowing where that pizza is, just from the smell of that pizza.

Erik, 19:22 – We’ve talked about the inspiration and the philosophical premise behind your research and work. Maybe let’s talk about the field you’re operating in or the fields you’re operating in – bioengineering and physical biology. Maybe explain what they are in a distilled fashion and why they are important.

Manu, 19:47 – I mean, let me just say this – in science we tend to pay too much attention to fields per se. These fields and these words are interesting architectures for organizing the administrative process of how science is done. Beyond that they really don’t have that much value, other than the fact that when the budget comes out from somebody who’s paying for this, they have to still assign things to it. I personally value, quite literally, there are sets of questions we are excited about, and we’re applying both physics and engineering tools as well as known biological tools to that problem. Just because this tradition of applying engineering and physics viewpoints to biological questions, it’s not so new after all, but it’s much more accepted at this time and that’s what these two fields are. Bioengineering being able to apply engineering ideas, the idea of learning how to make stuff. And in that process learn something while bio-physics and physical biology being the fact that much of laws of physics are things that biology has to abide by. And when you ask the question that way, many puzzling challenges become quite distilled and you can ask some very precise questions that were vague without that framework. I think the way that I think about how the lab is structured and how the types of problems that I care about, some of them are just very basic biological questions, which are truly just very fundamental. And then the other aspect of that is what I kind of call frugal science is this notion of making science accessible. Just that we have the privilege to experience science directly. How do you make that true for them, the 7 billion people on this planet. So those are the two themes that we operate in.

Erik, 22:01 – How would you advise a layman to interpret bioengineering? How would you distill it or explain it in more simple terms?

Manu, 22:12 – If you look at the eras of centuries and what the centuries have been dedicated to in the past, we along the way, as human culture evolves, we have learned to do things with a certain set of things. We learned first of all to handle inanimate materials and you know, we learned how to build things and that became the civil engineering and the mechanical engineering part of the world. Then we had an entire century dedicated to handling and manipulating information and that became computer engineering. We have not had – other than agriculture, for example, which is a pretty powerful one – we have not had the capacity to truly meddle with just like clay mold, biology. We get biology the way it comes and we take it or leave it, and yes we can do some amount of selection process to it to make it a little more palpable. But frankly it has been an open frontier that teases us. Bioengineering in it’s true form is taking biological matter as any other matter and being, having the capacity to mold it in what we would like it to be and in that process actually also deeply understand it. So that’s why biology and bioengineering have a true connection that in the act of trying to build with biology, you get to actually understand biology as well.

Erik, 23:58 – This is that the sort of cell and molecular level.

Manu, 24:03 – It can be at any level, frankly. You could do by bioengineering at the scale of the ocean, for example, where there is understanding the biology in the ocean and asking how much of it… What are the engineering principles, what are the fluxes, where is the transport process? If I turn this knob, how would this dynamical system behave? So it doesn’t always have to be handling molecules. It can be at any level of abstraction you desire. You have to ask the right set of questions in the framework of engineering. So in engineering we care about the robustness of a system. So I could ask a question: how robust is an ecosystem? Without knowing its molecular details, I just want to know, can I apply the same robustness principles to, say, how robust is a computer program to all kinds of challenges. Can I understand how robust is an ecosystem? How adaptive is a certain set of a system? So it’s much more about the framework rather than the level of abstraction you operate at. And yes, for the very first time we had gotten good at truly being able to engineer something in biology at an atomic scale. What’s very powerful about biological matter is it builds at using atoms, quite literally positions atoms extremely precisely to build its functional units. Bioengineering enables us to do that slightly differently. But having said that, it’s not true that you can work at any level of abstraction in these sets of systems as well. And actually it is important to work at different levels of abstraction because we sometimes understand when biology becomes chemistry, but we don’t understand when cells become animals or when animals become ecosystems.

Erik, 26:10 – So I have to ask you – when does biology become chemistry? What is that boundary?

Manu, 26:14 – It’s a very fascinating one. Clearly at some point of time, if you keep zooming in, laws of physical chemistry take over, but that’s a fuzzy boundary. What is a unit of life? Clearly it’s not a molecule. The molecule doesn’t know that it’s alive. Actually, a molecule is not alive because in isolation it can’t do anything. Clearly there is a certain collection of an ensemble of molecules that are capable of showing life-like properties, and very clearly in a cell we are happy associating the object of life to it. Many times people make this as a joke that – life is, we know it when we see it. It’s a very deep and an open question, at what exact scale would you define life. We don’t know what minimal life is. What is the smallest group or units of molecular entities that in anybody’s book would qualify just as plain old chemistry? How many of them need to be together to give rise to all properties of life? That’s an open question. We have examples of it, but these examples are so damn complex that they don’t reveal their secrets so easily.

Sachin, 27:41 – Connecting back to the theme of observation and questions to ask. There is research and problem solving, some experimentation, rather a lot of experimentation which goes into your lab. Some of this is highly unpredictable. Is there a process or framework you apply to your work?

Manu, 28:13 – Yeah. No, I think it’s clearly under the hood; from the outside it can seem like a madhouse. There is very clearly a way of thinking about what is a good question. Sometimes that’s just driven by, you are so flabbergasted by an observation that in all its forms and glory it makes absolutely no sense and that’s why it’s exciting. I think the framework that I enjoy is, one aspect of what I think about often enough, I do like to work in areas and problems which I believe are important, but at that same time as a society, we’re not paying enough attention. Whether that happens to be in basic science or whether that happens to be in the context of frugal science or making science accessible. I do believe that if there’s a question that somebody already… If I didn’t exist and somebody was already just going to tackle it anyway and crack open anyway, that’s not so exciting anymore, just because we have landed at the question already. I think the kinds of questions that I enjoy are the questions that are slightly ill-defined or are very well-defined, but we just don’t have a good framework until that idea pops out of asking those questions, or places where large fields have attempted things like that, but with a different framework than what we’re thinking about. To me, it’s another framework that we apply to a lot of problems, is that many problems that we end up choosing whether we like it or not are multi-scale. They have several different scales where phenomena at the smallest scales are influencing phenomena at the largest scales and that in itself is also a hard problem to tackle just because you are jumping so many scales, that every jump makes it highly unpredictable.

Sachin, 30:23 – This likely focuses on the selection part of the problem. How does that then transform into approaches to answer these questions?

Manu, 30:36 – What we do just personally is for very specific questions and problems we often start by building tools for that specific problem. Even with the philosophical hope that even though we might not be the ones who would crack open that problem, the tools we will build will enable others to open up those problems. I think that’s important. And you know, as physicists we often care about measurement tools with this philosophical view that only if you could measure something very, very well, you would better know what’s actually happening and when something slightly different happens, you would have the means to quantitatively say what that was. But often enough what to measure in these sets of problems is not so trivial. Secondly, how to measure is almost impossible sometimes for most problems. And that takes a giant lion’s share of time. But then once you have that, then either the entire problem cracks open right away or you have built a very powerful framework of tackling this and now many more people can engage in the process. It’s been true. I think ironically it’s been true for almost all kinds of problems that we worked on – tools have been an incredibly important aspect, but we don’t make tools for the sake of making tools. They were built for a specific problem that we cared about, and sometimes it ends up being that they are generally useful.

Erik, 32:10 – So to be a bit more sort of tangible, would you ever entertain sussing, for example, a p-value to determine a path forward for, let’s say, relevance in terms of findings, or do you apply other quantitative or statistical models?

Manu, 32:26 – I think we are very analytical in how we approach the questions we’re trying to answer. Of course, sometimes biology is a very noisy system and for the gut feeling it’s important to apply all kinds of tools that are accessible. But it’s not very satisfying in some sense. So the way we approach the path moving forward is often driven by early on in that system or in that phase of problems that we are excited about, we would make measurements. And it’s perfectly okay for those measurements to not make sense early on. Eventually as you start recapitulating the question from many different angles, it’s very specific to the kinds of questions we’re interested in.

Erik, 33:21 – So essentially a lot of the time the litmus test ultimately becomes or is based on your gut feeling?

Manu, 33:28 – No, I think the gut feeling is the beginning because in the end when you make an observation you have to have a hunch whether that actually is something novel and interesting and how much does it break your prior observations. That’s really where the gut feeling comes in. I think it’s an important thing that we should just accept. I mean at least I accept it personally, because there are certain things that I sense that, ah, there is something here even if I can’t tell you what that is because if I put the test for every possible thing that I know about this being true, this is not a trivial result to come out of it. The approach that we take, and especially just because we are so geared towards physical problems, in the end there is a very clear cut problem that is defined along the way. And then once the problem is defined along the way, all this gut feeling goes away. It’s either, this system was the right system to ask that question or it was not. And if it’s not, then we move on to the next thing. I think the art of science is not just about coming up with new ideas, it’s also about letting go of ideas. And that’s hard. Sometimes it’s just not the right time frame to ask that question.

Sachin, 34:57 – Yeah. Speaking of which, are there any frameworks or models that you may have picked up from your field or outside fields that may come across as surprising to you or even unintuitive, and you’ve been able to apply that?

Manu, 35:16 – I think this idea of thinking about all lens scales in a problem is something that’s very common in physics. And something that I find fascinating is that we zoom in on a problem we are working on. I think we are talking very abstractly about problems. I’ll just choose one that we currently have cracked open, which I’m very excited about, which is life in the ocean. So let’s just spend a minute and think about that. There’s plenty of life in the ocean. It’s ubiquitous, it’s everywhere. You take a bucket of water from the ocean and it is filled with billions of cells. A paradox that just struck us for a while was just the fact that if you look at much of this living matter in the ocean, it’s denser, it’s heavier than the water. And effectively gravity’s always on. And so things are being pulled down all the time and that should just imply that at some point of time the ocean should become barren of all life because it should just sink to the bottom of the ocean. Now I’m talking about small scale things. Of course, larger scale things in the ocean have the capacity to… literally they have appendages, they can move, they can swim. When you talk about smaller scale organisms, that is a question. It’s not clear whether a single cell can both either sense or actually act on that information. Here the framework was, look, how do I explain ecology at the grandest scale, which is the planet. Because on the planet, any single place you look in the ocean, anywhere you pull out some bits of water, you find life. We all came from the oceans. It’s actually an important framework to think about. That’s a really ecological question. While it’s origins are truly cellular and suddenly there is a paradox that you have to explain. So the framework of sometimes these multiple lens scales, if you add them all together, they don’t make sense. But it sets the question. And this question remained with us for a very long time. I’ve been thinking about this for a while until we cracked open, a kind of tool that has now allowed, we call it the anti-gravity machine, which is kind of an idea that allows us to suspend gravity or in some way emulate what’s happening in the ocean but in our lab on the tabletop. We made a realization that we needed a tool to observe the smallest scale of unit of life in the ocean, which is a cell as if it was completely suspended in the open deep ocean. That has never been possible before because you would, if you dive out in the ocean and you look at life observing microscopic life in the ocean is extremely hard. Observing it in the lab is easy, but then it’s not the same. You can’t ask that ecological question in the lab because the lab is very finite size, but we figured that out. So that was a tool. And then falls out a million questions. Now we can truly make observations where we can connect ecology to what’s actually happening at the smallest scale. And why something like that is important only comes much later. While studying the system, we made a realization that the ocean actually fixes 30 to 50% of all the carbon that we produce as humanity. So although we’re making an observation on just life at the smallest scale, individual cells, literally our society depends on the fact that the ocean is what are saving grace is. If the ocean was not absorbing 30 to 50% of carbon dioxide every year that we were pumping, we would have been way above the tipping point already. So it’s kind of this fascinating link of threads going from a paradox to a capability or a tool to truly grand questions, which we now have the capacity to answer because we are able to now perturb and ask this question of how does life at the smallest scale actually fix carbon in the ocean. This is kind of one way of an example where you go all the way from something that makes no sense, but it’s fascinating that it doesn’t make sense. I mean, how is it possible that life in this giant ocean would be there if it’s just being pulled down all the time.

Erik, 40:39 – You mentioned this notion of a tipping point. There are other notions, for example, in physics, like critical mass, that have explanatory power across domains and fields. Do you have any favorite mental model or concept that you like to apply?

Manu, 40:58 – Yeah, I mean, you know, I think it’s, it really is a function of you have to use all the tools in your tool box. There are lots and lots of these sets of ideas that have stood the test of time and have been useful. But there are so many of them that it’s, it’s unfair to apply. I’ll say something a little more critical about this – power laws is one example in network theory that physicists like to really talk about, that they look for power laws everywhere, but frankly there is a very famous debate that’s been going on for almost a decade now that we overdid it and we applied these notions a little too much. Similarly there is a renaissance right now in biology, where we have discovered phase transitions are an important way of asking a certain class of questions. But sometimes that should worry us as well that many of these frameworks – that truly are universal, they are very powerful – but you also can apply them a little too much because then you have a hammer and you just think everything is a nail, and we actually box ourselves in this terrible situation. Because if you do search on certain sets of these things, why is it that all these discoveries about these certain sets of ideas suddenly appear or co-exist? Some of those are real, and some of those are either already known and are better explained some other way, but just because everybody’s so excited about one kind of framework. So I think we should look for universalities. But we should be cautious of not just applying that everywhere because then we are blinded and we just follow the field. So yeah, I don’t really think I have any favorite. My favorite guiding principle is I want to work on toy problems, because it’s something that I can wrap my head around, and it truly has to encompass the spirit of the question I’m interested in.

Sachin, 42:57 – And goes with your superpower.

Manu, 43:00 – Yeah. It works well for me. Yes.

Erik, 43:03 – This is fantastic

Manu, 43:04 – I’m very simple minded in how I approach many things.

Erik, 43:33 – Let’s shift gears slightly. Let’s talk about frugal science, which we know is close to your heart; you’re passionate about it. It’s an incredibly fascinating approach. Let’s start with what is frugal science?

Manu, 43:45 I think frugal science for me emerges from a crisis that we are having in science and society per se, which is knowledge is fast becoming free to everybody and actually because of many people like you who work to make access to knowledge a priority. But science is about experience, and actually this goes hand in hand with observations, where the amount of information that’s accessible is exponentially increasing. But the experience of science, the true, genuine aha moment are still extremely expensive and literally inaccessible to a majority of the people around the world. Now whether you think about this in the context of healthcare; you can think about it in the context of just education itself. You can think about it in the perspective of ecological blunders that we commit. We need not just information be told from the top, we need society and almost everybody on our planet to have the capacity to make observations and actually experience science firsthand. It’s not just about, oh, I’m going to become a scientist and that’s why I need to experience. It’s just, it’s a way of life. And I think for me, frugal science has always been about this gap that I see, where, I mean literally we have 2 billion kids on this planet and half of them around a billion live under $2.25 per day for their families. That’s the average poverty line. So, we’re talking about half the talent on this planet does not even have the capacity to think about scientific systems, theories, and ideologies as a framework for living a creative life. And that’s not acceptable because primarily we are leaving plenty problems behind and we will not have the capacity to handle these sets of problems. So, it’s driven by this desire that science doesn’t happen in some fancy labs, in some big universities like mine, science happens on kitchen tables and in school rooms and anywhere and everywhere we live. But we just need to empower everybody to have the kinds of tools to be able to make novel observations. I think, but now the question is how do you do that?

Erik, 46:15 – And that bleeds into our next question, which is what are some applications you’ve developed in this space?

Manu, 46:22 – Yeah, we’ve been working quite a lot in this context of health and also education. Health from a perspective of, I often use this term – I was out in the field one time and a pathologist who has been working for the last 30 years there, he said after listening for a while, what you’re trying to do is diagnosis under a tree. And I actually liked that term quite a lot, is to truly being able to detect and diagnose diseases in the middle of nowhere. That’s one very practical application that we’ve been working on, and we have a lot of tools that we have developed along the way. I think another application that we’ve been working on in the broadest term is how to make people curious? One argument is everybody’s born curious, but the microscopic will has such an immense capacity to open our eyes to how the world actually is and not how we perceive it to be. The microscopic world truly has a power to astonish us within a fraction of a second. You could be looking at something and you’re like, eh, and you zoom in and it blows your mind. That’s something that I find very powerful because it’s such a pillar in science. We’ve been working hard on making that access to the microscopic world literally available to people. And that’s really what Foldscope is.

Erik, 47:53 – Yeah. Maybe let’s talk about the evolution of Foldscope. How did it begin and where is that project today?

Manu, 47:59 – Foldscope started almost seven, eight years ago. I was in Thailand, traveling. And I made an observation in the field, which was, I was sitting in the middle almost of a rainforest in a primary healthcare clinic, and I saw this really beautiful, fancy fluorescence microscope sitting in a locked room. This was a rabies clinic and I was starting to think about, wait a second, we’re out in the middle of nowhere, and this is exactly the same tool I use in my research lab. It was a realization that many a times scientific tools, we like to add complexity to them, but we don’t think of cost versus performance as a parameter. If you draw costs on the x-axis and performance on the y-axis, we are always just so focused on saying, oh, what’s the most bells and whistles I can attach to something. We forget that that’s impossible for that tool to then operate out of the bounds of a classical lab setting. That was the genesis of Foldscope, where I sort of put a challenge on ourselves. We will build the microscope that allows us to do sub-microns resolution imaging at a price point for a dollar. And you know, a normal microscope that you buy can cost tens of thousands of dollars. That was the bold statement. We made that plan without pinning ourselves or knowing how we would do it. Of course, I have been a fan of origami and flat manufacturing and so I started thinking quite a lot about that, and that led to a specific way of thinking about design primarily because flat manufacturing, we can quite literally build these microscopes out of flat sheets. And so manufacturing was always a part of this process. In the first phase, we made quite literally, we made 50,000 of these units, and we shipped them to people around the world. What was fascinating in that process was I thought we were making microscopes. But what we were truly making were communities. We were making communities of curious people and that was the essence of what we ended up doing. Of course, the tools are very interesting. But the community we created is actually far more powerful. And where we stand at this point is there is roughly around 700,000 Foldscopes around the world at this point in a hundred or 140-145 or so countries. And it’s the largest amateur microscopy community. And what’s powerful is literally any kid in the world at this point can buy a Foldscope anywhere for $1.75. It costs us roughly around that price point at this moment to manufacture it and we deliver it at that price. The reason we do that is primarily to make it accessible to the broadest of people. The way the program is supported is that there are several other classes of Foldscopes that we make that have other bells and whistles that allow us to truly subsidize the basic unit. Although many of the units are actually very similar. So that sort of creates a way for us to be focused on scale. And at this point, I started a company with my graduate student; it’s called Foldscope instruments. We manufacture these and one of the big things that we actually discovered along the way is what a profound number of problems people can apply tools like this to. And so once we transferred the ownership of problem solving to the people that engage with us, it became truly transformative, where I was not imagining, oh, this would be a good application to work on. Quite literally, tens of thousands of people around the world are working on completely independent sets of problems simultaneously using this as a core tool. They’re informing each other. We are evaluating each other’s work, but it is all grounded in the context of these problems. So we don’t have to imagine artificial context. The work is happening exactly where the problems are, which I find quite refreshing and powerful.

Sachin, 52:36 – Any other applications you’ve developed or you see reaching similar potential?

Manu, 52:53 – I think to me Foldscope is kind of an experiment where it was an experiment in technology transfer. It was an experiment in community-driven science. It was an experiment in trusting the power of communities globally. And there is a pipeline of tools that we are building that range in different sets of costs that we are also releasing along the way. So just like microscopy, we now have a tool on handling molecules in the field itself, and we are again releasing that as a modular tool. It costs us a little bit more, roughly of the order of tens of dollars, but it allows you to manipulate molecules at the nano-liters volumes almost anywhere and it’s a different kind of capacity. Just like we can play with computer code, we can play with molecules.

Erik, 53:58 – And where are you with the Paperfuge project?

Manu, 53:53 – That’s another version on the diagnostic side. With that, we are now scaling up the kits. So just like what we did with Foldcope. We will be announcing in a couple of months a program that allows us to get the current version of the kit to the broadest group of people, first phase. I think literally that’s what I meant when I said that Foldscope is an experiment because it allowed us to think about how to execute ideas like this. Paperfuge will literally be following a very similar footsteps and actually quite literally in the same community itself because we don’t have to reinvent the community.

Sachin, 54:59 – You’ll likely even grow the community.

Manu, 00:54:38 – Absolutely. Yeah. The community keeps growing actually. I mean we are always lagging behind. We’re now about to start a new manufacturing plant in India. We already have one plant in China. We are growing our capacity here. We’re trying to understand how to both share and interpret terabytes of data that’s coming out of these almost a million microscopes that are distributed now. We’re trying to truly understand what does it mean to measure or make measurements at a planetary scale. And so there’s a lot of just growth even in these sets of questions, where, as our community’s growing, we’re trying to understand how to connect many of these dots together. So it’s always a moving target. And of course we are trying to always make this financially sustainable. This is why this is not driven on any charity. Quite literally the entire operation is built on being able to sustainably run this as an operation.

Erik, 55:58 – And just to clarify, the Foldscope improves orders of magnitude on a cost-performance basis versus pre-existing equipment, right?

Manu, 56:08 – That’s correct. That’s correct. Yeah. And I think that’s a key insight that it suddenly has made microscopy where you can carry a powerful microscope in your pocket feasible. Its implications – I mean we have certain ideas in mind, but frankly I want our global community to figure out what are its implications. There are countries around the world, like in Tanzania, where we have sanitation programs where we are exploring what does it mean if kids are carrying a microscope in their pocket from a context of sanitation and hygiene. At a different place we are looking at, oh, can we detect fake drugs with an instrument like that, which is not what microscopy is used for. There are people measuring toxic plankton blooms, which literally kill people if you eat fish that is from those waters. A common phrase that I often think about is – it’s the pencil of microscopy. Once you have a pencil in your pocket, you can do many things. But if you were bound to a typewriter always that was bound to a desk always, you can imagine you are curtailing your ideas. Once you make that unbounded and you make that accessible, now we have a larger group of people who can play, who are allowed into the circles and that’s the power of that tool. I think for the most of our tools, we think about that as a goal. Every tool we make, it has to be very open-ended. It’s extremely important to us to think about – it’s not a tool for doing one thing. It’s very much like a computer. With a computer, you can do almost anything with it. It’s a very general-purpose machine, and that’s why these sets of tools are powerful to share.

Erik, 58:12 – We want to talk about another project you’re working on that I think we find the most exciting; it’s mind bending in a way. It’s the water-droplet computer. What’s the premise behind it and what is it?

Manu, 58:27 – It started as a very philosophical idea. That’s what I did my PhD on, the question whether it’s possible to build a computer just using water. They did give me a PhD because I had to prove both experimentally and theoretically that it’s feasible to build Turing complete computation, purely using drops of water. What’s interesting in kind of what you ask about what is the premise, it has a historical basis behind it, which is if you really think about information processing, it’s revolutionized every possible thing that you can imagine in our lives. It’s just so powerful. But when you think really hard about what is computer science truly. What is the core of these sets of ideas? You make a realization that every information processing mechanism that we have, whether it’s a computer that runs on electrons, or whether it’s a photonic chip that’s manipulating photons, at the heart of it to represent information, you need a little bit of physical material. So while we are talking our computers are running and if you could watch all these electrons are running around. So there is a physicality associated with information, but we ignore it to make the computer. We ignore the fact that electrons are running around and if in one fraction of a second they are in a completely different location. And the idea that I’ve been excited about is what if you don’t ignore it? Suddenly computer science becomes a principle of not just manipulating information but for manipulating matter. And ironically that is what we are really bad at. Everybody’s excited about 3D printers and things like that. It’s a serial processor that’s putting tiny dabs of material or glue serially. But if you look at your own hand that is at least a billion or more cells that have been organized, but there was no serial processor additively that actually put every one of those cells in that place. They got there using an algorithmic set of ideas. There is something common between your right finger and your left finger that it’s almost as if it’s code that’s executed. The idea of fluid computation, what I kind of call these the droplet computers, is that these drops not only have the capacity to compute, they also have the capacity to carry materials. When they compute, they not only provide us information, they literally transform themselves into the pattern that you desire as an output. So what we are exploring in the long-term – and this is a big goal I think in the next five, ten years we’re trying to achieve that – is building a system that allows us to build using computation like this; where quite literally I can program and compute a fractal but you don’t just get the Fibonacci series, you get the Fibonacci structure. That’s the big idea.

Sachin, 1:02:02 – Could you speak to the broader work which is happening in physical biology and the areas you are working on outside of what you are doing in your lab?

Manu, 1:02:20 – I think there has been a renaissance in what I call physical biology. The fact that biologists are paying attention to physics is really fun and heartwarming. It was that way for a long time. But it’s actually quite eye-opening in terms of just every field in biology, the physical context really matters. And finally we are getting to a point where we are truly making precise measurements and trying to understand what these measurements are telling us. So, I personally get very excited about instruments and tools that allow you to see something that could not be seen before. So that’s sort of what I would argue is something that I believe is quite valuable in that field, that we’re finally coming to some conversions that we agree on the kinds of questions and we agree on the kinds of approaches.

Sachin, 1:03:05 – What role has technology played in your research work?

Manu, 1:03:11 – I think it’s to an extent that we are bounded almost completely by our technological capabilities. I think just personally I like as a guiding principle, I like picking up on the history of science because that’s a really phenomenal guide. Where we are is not just an accident. It’s a very series of historic things that happened along the way. You know to me that also teaches us quite a lot about where we can go. So technologically that’s been really fun where sometimes use the sets of technologies that may be in current day and world or call cutting edge, but sometimes we actually use technologies that should have existed but just don’t because nobody’s working on it and they are equally powerful.

Sachin, 01:04:09 – And that’s very pertinent.

Manu, 1:04:12 – Yeah, it’s, it’s kind of fun that what is in the radar is always dependent on just what’s the most common things. History of science teaches us that there is a lot already that’s been done.

Erik, 1:04:38 – Maybe compare something you’re able to do today that was not possible in your lab say 10 years ago and how technology improved your research process?

Manu, 1:04:52 – I think the instrument that I was telling you about that allows us to watch a single cell travel as if it is in a completely unbounded ocean requires us to track organisms that are moving extremely fast. And so quite literally, we’re doing real time, or actually almost 3D, 200 Hz scale imaging on moving objects. Figuring out what the object is doing, which happens to be living systems, and literally building drive through real-time control systems such that we can always track an object like that. So finally for the first time we can see the entire lifespan of a single cell in an unbounded ocean. That requires us to literally have all the kinds of gaming stations that are accessible. This is only possible because we have access to a new kind of a lens, which is a liquid lens that dynamically changes its focal planes at 200 Hz. We can build them cheaply and easily because of things like Raspberry Pis and other things that exists now in the world. So it’s kind of an interesting juxtaposition that in order to understand these biological systems, we have to rely on extremely high feedback and very fast electronic systems that are only possible in the last 10 years.

Sachin, 01:06:37 – What motivates you?

Manu, 01:06:39 – Oh, I think lack of sleep maybe.

Erik, 1:06:58 – How do you allocate your time?

Manu, 01:07:13 – I don’t actually. I am pretty much, if something I’m excited about, I don’t think about what I’m supposed to do, but I do what I want to do at that time.

Erik 1:07:17 –  A flaneur, a scientific flaneur.

Manu 1:07:19 –  Cool term! Yeah, I like that. Yeah.

Sachin, 01:07:07 – Which non consensus views do you hold near and dear?

Manu, 1:07:35 – Everybody’s a scientist. We are all born curious and we all have the capacity to infer what this world is really like only if we look at the world the right way. And this is a global capacity that just human beings have.

Sachin, 01:07:31 – What’s the biggest trade off in your professional existence?

Manu, 01:08:01 – Oh, the trade-off is I wish I can spend more time with my kids.

Sachin, 01:07:41 – What are you currently reading?

Manu, 1:08:07 – I was giving a talk at Berkeley and a friend of mine who’s a professor in the math department gave me a really fun book that I’m reading. It’s called Exploring Curvature. It’s a book about differential geometry. And there are a couple of problems in differential geometry that I’m working on. But the book is beautiful because although it truly is about differential geometry, it is written with very simple little experiments that you can do to understand differential geometry. It is roughly around 150 little experiments. My favorite one in there is one using a bottle of soap, kind of the dishwasher soap, to teach a very famous theorem in differential geometry. I’m actually trying to finish this.

Sachin, 1:08:59 – What projects are you currently working on?

Manu, 1:09:04 – There’s a lot of stuff in the pipeline now. I think the gravity machine is one that we will be announcing very soon. Maybe in a week or two we’ll be posting the first paper to watch single cells as if they’re unbounded in the ocean. So that’s something that I’m very excited about recently.

Sachin, 01:09:00 – And how can listeners learn more about your work?

Manu, 1:09:28 – I think rather than learning more about my work, I would be excited about listeners to get out there and polish their observational skills and experience science and not just read about science. There are many tools like Foldscope that enable people to observe. It’s very powerful because sometimes we think science is so inaccessible; it’s far away; it’s only, oh, I’m not smart enough and all that stuff. These are excuses we make to not make observations. And I think all that does is just it hides many of your potentials that you have as a curious person. So that’s what I would hope the listeners to take away from this whole thing.

Sachin, 1:10:15 – We hope you enjoyed the conversation. For more information and latest updates, visit us at Luminary.fm or follow us on Twitter @Luminaryfm. Please subscribe to the podcast, pop us an iTunes review, and share with friends. Don’t forget to check out the show notes. And a quick disclaimer: The views and opinions expressed in this episode by the hosts and the participants are solely those in independent capacity and do not in any way represent the views from any organization, company, or management they may be associated with. And thank you for listening.