NEB Podcast Episode #15 -
Interview with Ron Weiss: Advances in Synthetic Biology

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Transcript

Interviewer: Lydia Morrison, Marketing Communications Writer & Podcast Host, New England Biolabs, Inc. 
Interviewees: Ron Weiss, Professor of Biological Engineering, Massachusetts Institute of Technology


Hello, and welcome to the Lessons from Lab and Life podcast. I'm your host, Lydia Morrison, and I hope that our podcast offers you some new perspective. Our podcast today focuses on the value of pursuing a good idea, sometimes even despite the recommendations of your mentors.

I'm joined by Ron Weiss, professor of biological engineering at MIT and widely acknowledged as one of the founders of synthetic biology. His lab's work focuses on assembly and delivery of genetic circuits, mammalian synthetic transcriptional regulation, micro-bio robotic communication, and in vivo biosensors, all of which seems, quite frankly, futuristic and awe-inspiring.

Hi, Ron. Thanks so much for being here today.

Pleasure to be here. Thank you.

Could you tell our listeners a little bit about yourself and the kind of research that your lab does?

Yeah. I'm actually a computer scientist by training. I got my PhD from MIT around 2001. As a computer scientist, I was initially interested in things like digital video and internet and searching and things like that. Half way through my PhD, I decided to switch gears and rather than programming computers, I wanted to start programming cells.

I ended up doing a PhD in an area that turned out to be synthetic biology. I then had a faculty appointment at Princeton 2001 to 2009, in which I set up a lab and we did a whole bunch of work in synthetic biology. Then I came back to MIT 2009 and faculty positioned there and also created the MIT Synthetic Biology Center. That's basically what occupies most of my time is doing synthetic biology.

Absolutely. Could you tell us how you currently define synthetic biology?

Yeah. The meaning of synthetic biology is different for every person that you talk to. I would say for me, synthetic biology really started as this notion of building regulatory devices, characterizing them, and then understanding how to put them together to create systems of interactions. The notion of system-level engineering, of regulation activities inside the cell, to me really represents the core of what's synthetic biology is.

I would say that over the years, the definition for many people has expanded, whether you're including various kinds of other genetic engineering mechanisms, building various kinds of genetically encoded devices to act as sensors, as regulators, as actuators. Also, trying to understand how to apply them to different application areas, whether it's metabolic engineering, cancer immunotherapy, vaccination, and so on.

Also, in addition to that, people are looking not just at doing it inside cells, but also people are looking at doing synthetic biology in cell-free systems. People also termed this notion of creating minimal organisms. Some people view that also as synthetic biology, but it's kind of expanded to include many of the things that we do in biological engineering, like the creating of new biological systems.

Moving from computer programming to synthetic biology seems like a great leap, especially when synthetic biology was a new and emerging field. I don't know how established it was in 2001. Can you talk about the decision-making process and what led you to make that change in your career?

Yeah. Basically, I was involved in this project called amorphous computing. In amorphous computing, this was a computing-based project, and the idea was, can we imagine creating very small computational elements that we can actually embed everywhere? Like smart dust, smart paint, and so on. It was kind of cool ideas about how we can make computing really pervasive and present everywhere. This was a project that was led by Gerry Sussman, Hal Abelson, and Tom Knight. These essentially were my three PhD advisors.

I was trying to figure out, how would we program millions or billions of little computing elements? They're not going to be highly functional. They're only going to be able to interact with their neighbors. We're going to have a whole bunch of restrictions on them in terms of their power. I said, "What is similar to that?"

The thing that jumped right into my mind was biology. Basically, biology, you have a situation where you have millions or billions of little fragile computing elements interact in interesting ways. They lead to very robust behaviors. What I wanted to do was basically look at biology, and actually specifically look at embryogenesis, and try to understand how processes in embryogenesis can lead me to think about programming amorphous computers. I started doing all kinds of simulations on neural tube formation and somite formation, all these things that look like biology. They weren't exactly biology, so I wasn't trying to exactly recapitulate everything that happened, but trying to do things that look like biological systems.

I remember some days I was thinking to myself, "Rather than trying to basically understand biology and use that as a mechanism to program computers, I want to actually flip the arrow and take what I know about computing and actually use that to program biology." Basically, do a 180 degree turn. Then I went to my advisors, Tom Knight and Gerry Sussman and Hal Abelson, and they said, "Awesome Ron, but I think you should really finish your PhD and what you're doing. You were getting really close. Then after that, when you're a post-doc or something like that, you can work on these things." That was exactly what I needed to hear to say, "Okay. I really want to get into synthetic biology." Just basically go completely against my advisors' recommendation.

What I did then is I joined Tom Knight, and he was setting up a wet lab in the artificial intelligence lab at MIT. I helped him set up a wet lab and basically worked for him as a graduate student in building all these genetic circuits.

Would you consider yourself more an engineer tackling biology problems or a biologist using engineering techniques?

I would say definitely the former. I'm an engineer in passion. I love to think about how to take things and create new behaviors. This is the thing that really gets me excited. How can I essentially program new behaviors into either existing systems or create systems with new capabilities? I'm certainly curious about science and biology and I'm fascinated by how the world works around me and want to learn about that, but then I want to use that information to figure out how I can create things that have never existed before.

That's really interesting. Did you find that as a child you were always extra curious and looking to make those connections between things that maybe seemed unconnected to the visible eye?

Yeah, possibly. I've always been interested in this notion of programming new things. When I was growing up and computers were not really all that common, even as like a seven year old, I began to program computers and mainframes-

Wow.

... and use like punch cards in these mainframes. I was just fascinated by the notion of, can we program either computers or things around us to do new things?

When I think about computer programming, I sort of think about the on-off toggle or maybe elements that might attenuate something, turn something up or something down, but obviously biology is a whole lot more complex than that. How is it that you're able to take those on-off principles and move them into the world of biology? How do you understand the breadth of the changes that you're making when you do modulate one of those things?

I teach a course about that.

Oh yeah?

Yeah. It'll just take one semester and you're ... No, so-

Sign me up.

Okay. It's online, if you want to ... It's Principles of Synthetic Biology.

Oh cool.

It's online on edX, which is a platform, and I co-teach that with Adam Arkin.

Awesome.

It's a really fun course. We have our next iteration, the third iteration of that, is going to be this summer. Please join us.

I would love to.

We can talk all about that beyond a couple minutes. At a high level, when I started synthetic biology, the first thing I was trying to do is do these kind of on-off systems. Basically, do these switches, do these NOT gates, these AND gates, these OR gates, and really try to make biology be able to perform on-off operations. It does. It's not like this is something that biology's never done before. Biology, in certain situations, acts in a discrete fashion. There are many situations in biology where things are either on or off.

Sure.

As an approach, I figured the best place to start is with behavior that I can understand and try to implement that in biological systems, while importing and understanding enough about biology and understanding how biology does its on-off and using the principles that biology uses to make on-off, gates, switches functions, use that for my own programming purposes. I would say a good portion of the first five, seven years that I was working in synthetic biology was really focused on engineering the best on-off systems that we could and then creating more and more complex on-off systems.

Even from day one, I realized that biology does some on-off, but it does a lot of things that are more graded, more temporal, more noisy, kind of more stochastic, less deterministic. I felt that once we gained enough understanding of how to control the on-off systems, we would begin to explore the more complex things that biology does and then begin to try to understand how we can use those for engineering purposes.

For example, one of the things that we like to use now is noise and heterogeneity as engineering tools. We actually have several systems where they wouldn't work otherwise, but by being able to incorporate specific elements of noise and heterogeneity, we can actually take a non-functional system and make it actually functional in the biological context.

Which probably mimics natural biological function more closely than a straight on-off switch would anyway.

Exactly. We've been transitioning overall as a lab to try to incorporate more engineering principles that are based on biological understanding, biological substrate. What can biology do really well? What kind of challenges are faced by biological systems? And be inspired by natural designs on how we create our own programmable systems.

Could you offer a couple of examples of everyday applications of biological circuits that might be available in the near future?

Near future? Okay. I guess we should define what near future means first. For some x number of years, where x will remain an unknown variable.

Accepted.

Okay. To give in that constraint, I would say that there's a certain set of things where I would say synthetic biology can offer like practical solutions. I would say that for industrial biotech, being able to genetically engineer organisms for bio-manufacturing is becoming a reality, and being able to incorporate fairly sophisticated mechanisms for either engineering small molecules, other kinds of high value compounds, engineering bacteria or yeast to be able to do that is becoming real. Then also, engineering mammalian cells to be able to manufacture therapeutic proteins. I would say that that's also really becoming a reality. I think for those practical applications, that, I would say, is rather near term.

I think the next step would be for synthetic biology to be used therapeutic applications, so being able to create gene therapies that have on-off switches and safety switches to be able to turn on therapeutic genes inside a human, either to fight rare diseases or even to fight cancer. There's a variety of health-related, or vaccinations, but there's a variety of health-related applications that I think could really benefit from the control that synthetic biology provides. That's gene therapy type of applications and also cell-based therapies for being able to, again, target cancer, being able to target other kinds of rare diseases. I would say that that's an aspect of synthetic biology that's definitely moving forward. You can see almost in the near term that those things are really going to be available and can have a real impact in the world.

Now there's kind of the longer term vision of, "Can synthetic biology be used in other environments, in other situations?" That's more vague and unclear, but for example, one of the things people talk about is, "Can you use synthetic biology to create bioluminescent trees?" Those can be used instead of streetlights, as like an environmentally friendly way of addressing the resources, the limitations in mother earth.

Wow. You would have individual cells within a tree express a fluorescent protein or something like that?

Actually, maybe even the entire tree would be genetically engineered to express bioluminescent proteins, and maybe do it only at night so that it can save its energy and store up energy so it can actually bioluminesce even brighter at night.

Right, and then offer those advantages that a living tree offers to a city rather than using electricity and obviously be a much more sustainable practice, I guess.

Exactly. The whole notion of the environment and sustainability, I think one can think of the fantastic but possibly exciting opportunities for synthetic biology. Can we engineer plants that can help the environment and can do environmental remediation? Can we engineer microbes to be able to do that?

Like to clean drinking water or something like that.

Yeah, to purify. Actually, I have a colleague of mine who's working on desalination, to actually engineer plants that can purify water instead of these really expensive billion dollar processing plants right now, talking about actual construction of a building and pipes to do that. Can we get biology to do that? Plants are great. Why not engineer them to help us in further ways?

Wow. It seems like there's a plethora of broad ranging applications for synthetic biology. So someone's excited about the topic and wants to learn more or thinks that that might be a career for them, how would you suggest that someone start down this career trajectory? Are synthetic biology programs pretty prevalent across the United States or around the globe?

I think the educational material is improving, but it's not where it should be yet. For example, there's some beginning examples of textbooks. I would say look around, try to find existing online material. There's actually an increasing amount of online material that's available to help you get into this general area.

Another really useful thing is try to find an iGEM team. iGEM is this International Genetically Engineered Machine competition. If you're going to certain high schools or certain colleges, they have iGEM teams, or you can form your own iGEM team in high school or in college. That happens all the time. That's a great way to get introduced into synthetic biology. iGEM is basically this really cool competition where teams of students just get together, learn about synthetic biology, and then come up with their own crazy, fun ideas. Everybody gets together in this iGEM jamboree and people present their ideas to one another. That's a really fun way to quickly engage yourself with the rest of the community.

In addition to that, there are existing programs, especially in various universities around the country and other places, Europe, Asia, Australia, that are really popping up and are looking to develop a curriculum in synthetic biology. Those are beginning to sprout in several places around the world.

That's so cool. Just so all our listeners know, we'll have lots of links in the transcript of this so that they can find resources like your online course and more information about iGEM teams.

One question that I wanted to ask you about, Ron, is the development of organoids. I just sat in on your seminar, and you talked about programming IPS cells, the induced pluripotent stem cells, to follow a specific path to a specific lineage to, say, create an organ. Can you tell me a little bit about that story? Then I'd love to know if what we're talking about is like a liver in a Petri dish or if what we're talking about is a group of cells that resembles a liver in a Petri dish.

We're trying to figure out exactly the answer to that, but in terms of a liver in the Petri dish, it looks like it actually has structures of an actual liver.

Okay.

It's a collection of cells with structures such as vascular networks and bile ducts and things like that that actually resemble what you would find in an actual liver in a human being. What we try to do with what we call programmable organoids is this notion of, as you mentioned, the IPS cells, the induced pluripotent stem cells. We take them. These are actually ... One thing that's interesting about them is they're patient-derived. You can take any individual and take this person's fibroblasts or skin cells and then reprogram them to create the IPS cells. That's a technology that most labs around the world are essentially able to do. It's not completely trivial, but it's certainly something that's accessible to almost everyone.

The cool thing is you can take a person's skin and then reprogram that to IPS cells. Then we come in and we embed further genetic circuits in there that then allow us to take these IPS cells and then develop them into possibly maybe other organs in your body, ultimately. This would be a genetically controlled IPS cell that basically proliferates, so it begins to replicate itself, and then we embed instructions in there, genetically encoded instructions, that now tell that IPS cell how to develop. For example, we can tell it now to make a liver.

As you can imagine, making a liver is not so trivial.

Yeah. It sounds complex.

Yes. It's a very complex process. What we do basically is we provide the right push to the IPS cells. We don't tell it to ... We don't control directly every single interaction that happens in every individual cell and the interaction between every set of neighboring cells. What we do is we provide the right push. Basically, our first push to the IPS cell is tell them become endoderm and mesoderm. Basically, from that initial pluripotent population, we now get a population of cells that are meso-endoderm, and then we can even tell some of them to become endoderm and some of them become mesoderm. We provide the right push, and then the cells have natural pathways that are activated due to our genetic push so that they execute these very complex programs to create an endoderm layer, to create a mesoderm layer.

The cool thing about biology is that it can continue to develop. For example, what happens in our organoid system is that the endoderm continues to develop towards things like hepatocytes and cholangiocytes. Those are basically the main cell types that are found in the liver, but the mesoderm also continues to co-develop alongside the hepatocytes and cholangiocytes and we get vasculature to actually develop from the mesoderm layer. As a result of that, we're able to recapitulate embryogenesis such that we, from the initial IPS population, we get basically co-development of all the cell types that are known to exist in an embryonic liver. We get this very intense vasculature that's completely embedded in this liver-like structure.

That's really interesting. How far do you feel like we are from taking something like that and being able to transplant a liver that was grown in a lab into a human, and such that it's fully functional?

We may not be that far from that. One of the things is that we actually are using the liver organism right now. They actually have an immediate use to be able to perform drug screening and evaluation of drug candidates. There's a big movement right now in biotech industry and big pharma to be able to use organoids to either replace or augment animal trials. Rather than basically exposing a mouse or rat to a particular drug candidate and try to understand how that mouse or rat responds, and does it have safety, does it have efficacy in a mouse, in an animal model, there's a lot of excitement about this notion of being able to create human organoids in a Petri dish and basically exposing them to the drug candidates and asking the question, how does this human-derived liver, human-derived kidney, human-derived brain or something like that, how does that respond to particular drug candidates? That's going on right now. There's an interest right now in being able to use that. There's an immediate use for programmable organoids.

Beyond that, something I'm obviously very excited about in the future is being able to embed these programmable organoids as a therapeutic modality. If somebody has some kind of liver disease, can we take that person's skin cells, reprogram them to IPS cells, and then grow an embryonic liver in a Petri dish, and then transplant that into a human to be able to counteract the liver disease? That's something that may be possible ... Again, x number of years where x is not a huge number.

Yeah. That's pretty amazing technology to think that we would be able to take that sort of level of programming to create an organ that was of such a high quality that it could be transplanted into a human. In terms of the drug screening, does that ... Would the organ level response to drugs be indicative of overall toxicity of treatment?

Yeah. The cool thing about being able to have organoids in a Petri dish is that you can have the ability to expose them to various kinds of drugs and very precisely see how they respond to it in real time. Some of the things that we're doing is embedding genetically encoded sensors for a variety of biomarkers that are indicative of various pathways and how they respond in disease-like ways or in harmful ways.

For example, one of the experiments that we did was we asked the question, "We have a liver organoid. What kinds of drugs might have an impact on liver?" We're like trying to think about this and realized an obvious one is actually Tylenol. Acetaminophen actually is toxic to liver at high levels. What we did is we embedded into the liver a sensor for a particular micro-RNA, micro-RNA-122. Basically, we have a liver, and now if you have abnormal levels of micro-RNA-122, it fluoresces in red. We were able to then add Tylenol at various concentrations and the liver was turning red in real time.

That's crazy.

Yeah. The notion is that a programmable organoid would be able to tell us in real time how a drug is affecting it and which particular pathways are actually being affected. There's going to be a tremendous amount of information that could be provided regarding the biological mechanism of action of these drug candidates.

Wow. That seems like a tremendous amount of insight to be gleaned from having these resources available really for pharmaceutical companies, especially in terms of not only not having to treat the small mammals with these drugs, but also in terms of having really a better model system for human treatments.

Yeah. Thinking about taking that from individual organoids to possibly multiple organoids that are interaction because some diseases come about from interactions with just a single organ, but a lot of them come about from interactions between kidney and liver or pancreas and liver or interactions with the immune system. There's actually colleagues of mine who are also working on creating this notion of human on a chip, where you actually have multiple interacting organoids and really being able to test the impact of drugs on the entire system, not even just an individual organoid.

Wow. Thank you so much for joining us today. I feel like you really offered both myself and our listeners a glimpse into the future of what synthetic biology can really offer medicine and the world at large.

And streetlights, right?

And streetlights. Exactly. I was trying to figure out how to work that in.

Yeah.

Thanks so much.

Great. Thanks for having me.

Hopefully you enjoyed listening to this episode of our podcast and that you're as excited about the medical and environmental benefits that synthetic biology can enable as I am. As always, the transcript for this podcast contains links to learn more about Ron's research, , iGEM, and more.

Be sure to tune in next time when I'll be joined by some of the 2019 NEB Passion and Science Award winners, who are working to bring STEM education and experiences to children and adults around the world.

Content is covered by patents, trademarks and/or copyrights owned or controlled by New England Biolabs, Inc. For more information, please email us at [email protected]. The use of these products may require you to obtain additional third party intellectual property rights for certain applications.

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About your host:

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Lydia Morrison
NEB Marketing Communications Writer

Lydia is a scientist by training and a communicator by nature, and has a knack for asking one too many questions.

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