Science TED Fellows

More to life than DNA: Fellows Friday with Sheref Mansy

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American synthetic biologist Sheref Mansy is working on constructing artificial cells that mimic — and “talk” to — biological cells. In this fascinating conversation, Mansy weaves through the question of what does and does not constitute “life,” the possible practical applications for his work, and how conversations with artists have opened up concepts that feed into his research.

How would you describe what you do?

My laboratory — the Mansy Lab at the University of Trento — builds artificial cells, or cellular mimics. What distinguishes us from other people in this field is that, typically, people begin with something that is already alive and then they try to change the behavior of that already-living thing by changing its genes. What my lab does is a bit different. We start with things that are not alive. So, protein by itself is not alive, DNA by itself is not alive — but somehow, when you put these things together, under the right conditions, you get life. Nobody knows how that is, and so that’s what we’re trying to figure out. I guess you’d say we are exploring the boundary between living and non-living. What does it mean for something to be alive?

So if DNA in itself is not alive, what is it?

It’s just a molecule, which scientists can build in the lab. That was one of the nice things that the Venter Institute showed: you can build an entire synthetic genome, and it’ll function like a natural one. But what his work didn’t really show was what exactly is needed to get that DNA to sort of kickstart life. It’s nice work, I have no criticisms of it. But it leaves a lot unknown.

For example, the genome that was synthesized by the Venter group was relatively small. But still, approximately one-third of the genes of this genome provided unknown function. So it’s a very black-box approach. We know this stuff is needed, but we don’t know why. With the approach I’m taking, in which we build from the bottom, piece by piece, I hope that we will, in the end, get to a sort of cellular lifelike system in which we know why every single component is needed.

Can’t you go backwards and take out one gene at a time?

Many people do that as well. It’s a legitimate approach, but there are a couple of limitations. First of all, evolution is extremely complex. It’s not a linear process that can always be easily traced. You can go back a bit, but it’s hard to really get back to the beginning.

I think building an artificial cell with biological parts and studying the origins of life are two separate fields. I try not to talk about the two at the same time, because I think it’s confusing. A lot of times people assume that by going backwards — going back in time by knocking out genes — you’re making a simpler organism. But in fact, you’re perhaps only going a bit back in time. The simplest organism you could theoretically reach with this approach is still extremely complex, too complex to reach in a single step from a collection of molecules on prebiotic Earth. There must have been much simpler, living or lifelike things in between that we don’t have a trace of, and we haven’t figured out yet how to build in the lab.

Non-living cellular mimics built in the laboratory. Photo: Paola Torre

Non-living cellular mimics built in the laboratory. Photo: Paola Torre

What is the difference between life and not life?

This is actually something that there’s no clear answer to. “Life,” in many ways, is not a scientific term, or at least there is no scientific definition of it. This is one of the obstacles or challenges that we face in this field. I often contrast what we are doing with traditional engineering, because people like to say that our field is a field that engineers life. If you ask engineers to make a plane, or to build a car, they know exactly what to build. To build life — it’s an ambiguous term. To give one classic answer, many people say life is something that can self-replicate. But there are sterile animals, and none of us would say they’re not alive. There are salt crystals. Even table salt, under the right conditions, can form multiple salt crystals. So it’s a form of replication, but nobody would say that table salt is alive.

What about plants that can’t pollinate themselves?

You can find lots of examples like that. This is what happens with every definition: Every time somebody says “life is” the following, you can find living things that don’t fit, and non-living things that do fit.

So DNA, by itself — I mean, you could say DNA plus maybe some proteins can replicate, but, you know, is it self-sustaining? There are so many different characteristics of life we could go through. To be honest, I find it both interesting as well as frustrating, because when you go to conferences in this field, sometimes you get in a situation where people are just fighting: “Well, but that’s not really life! Why are you building that?” The thing I find frustrating about that attitude is that there’s not enough good science in this field, so one wants to sort of systematically try to make progress. That’s hard to do if all you do is fight over definitions.

What is the field called?

A very good question! I think, broadly, we do fit into synthetic biology, but typical synthetic biologists do what I said before, which is start with something that’s alive, and they tend to really focus on technological applications, such as how can you engineer E. coli or yeast to make diesel for your car. Practical things like that.

People in my field do try to do some practical things, but we’re often more concerned about fundamental science questions. We are broadly within the field, but we’re not in the mainstream part of it. Some people like to use other terms, like artificial life, for example. If prebiotically plausible molecules are used, then it falls under origins of life, of course.

Are you thinking about applications for what you do?

I do think that there are applications. So right now in my lab, we are building artificial cells in a way inspired by the artificial intelligence community. I guess I like to refer to it as trying to build a cellular Turing test. All living things communicate chemically, so we’re trying to build an artificial cell that can speak the same chemical language as a natural cell, and then we want to ask whether natural cells understand that ours are artificial, or do they think that they are talking to other natural friends, a natural neighbor? So can we trick E. coli, for example, into thinking it’s talking to another E. coli.? If we keep getting better and better at this, then perhaps they will become indistinguishable, not only to a bacterium, but to us.

But while this is a fundamental science question, I think it could have technological applications. Cancer cells secrete different molecules from non-cancer cells. So, in the future, we should be able to not only identify target cells, but perhaps we even could get our artificial cells to synthesize drugs in response to it. Perhaps it could even use local resources that are already provided in the body, so you wouldn’t have to actually, you know, take medicine, but have a little artificial cell that just manufactures it when needed, in the proper place, so you’re not flooded with toxins. Those are the kinds of things that I could see as applications.

Photo: Sheref Mansy

Photo: Sheref Mansy

How did you get into this field, and end up going from Ohio to Italy to pursue it?

I had the fortune of doing my post-doctoral work in the laboratory of Jack Szostak at Harvard. When I was there, I was researching the origins of life, which is the idea of building a cell from chemistry, restricted to the kind of molecules that could’ve existed on Earth before there was life. It was a lot of fun. I mean, it was amazing to me how much lifelike behavior you could build with simple chemistry, with a small number of molecules. I often liked to say that with just four simple chemicals, you can begin to get a chemical system that feeds and replicates and potentially even divides.

This was fascinating to me, and the time I spent working with Jack made me realize that it should be possible in the not too distant future to build cells from scratch, by starting from basic chemistry and physics. I mean, why not? This is what has inspired me ever since. In fact, I think once you start working on origins of life problems, it’s difficult to completely leave it behind. Thankfully I get to continue such work through the Simons Collaboration on the Origins of Life.

While I was at Harvard, I discovered that there’s a fantastic organization called the Giovanni Armenise-Harvard Foundation, which funds a lot of science at Harvard Medical School. They also have a career development award, and if you win this award, you get a nice startup financial package to build a laboratory in Italy. I found out about this opportunity, I applied, I got it, and I was happy to take the adventure. It’s been a great experience.

There are lots of people at TED who are generally interested in the concept of how life could have begun, the definitions of life, and how to distinguish non-living from living. One of the pleasant things about TED is you really have people who have very broad interests who have thought about it a lot, and it’s fun to hear these perspectives. In fact, and I’ve realized this now for some time, but the first time I spoke with artists about this topic, I was shocked at how much artists think about it, and it’s been fruitful.

Really? How?

I was involved in working with artists in the past, and one of the things that struck me from those conversations is that they often do think of life in a different way. Scientists, for example, have a definition that they like to quote: “Life is a self-sustained chemical system capable of undergoing Darwinian evolution” — which is a very precise definition. It’s nice, because it gives us something to work towards. But I remember the first time I started speaking with artists, I really started to realize how much the definition doesn’t resonate with anybody except for us. That had an effect on me. In fact, I would say that several of the concepts in my work now — trying to deceive natural cells with artificial cells — were formulated by talking with people who are outside of the field, but who think about life and think about science.

None of them actually told me, “What you’re saying is wrong.” But they weren’t fixated the way scientists seem to be on DNA and RNA. I think it makes sense in many ways, but it’s a very narrow view of life. There’s a lot more to life than just DNA. And I found that artists don’t fixate. They don’t obsess over this single molecule.

That’s not to say that there isn’t good reason to thoroughly explore nucleic acids. DNA and RNA are the means with which evolution works and are responsible for all of the life on Earth. Also, we know well how to work with these molecules in the lab, so the research is more easily accessible. And of course you’re going to exploit what’s available. Artists don’t have that constraint, right? So I think they’ve thought about it a little more broadly.

Photo: Sheref Mansy

Photo: Sheref Mansy

Are you having conversations with the other Fellows who are looking for life on other planets, like Louisa Houcke, who is looking for analogs to life on Mars in extreme Earth environments?

I’ve not spoken to her yet, but I would like to. Again, I think that scientific bias is a problem with many of these searches. I believe that NASA puts some effort into looking for extraterrestrial RNA sequences based more or less on the kind of RNA sequences that we have, so it’s difficult. What can you do? I certainly am not trying to criticize. It’s a difficult problem. But, we tend to focus in on narrow slices, and there’s a lot more out there.

How will you know when you’ve succeeded?

We’re trying to do something that hasn’t been done before, so we’re starting at the really most simplistic levels. We’ve designed our system to work in a way in which our artificial cells turn green when they ‘hear’ E. coli speak, and E. coli turns red when it hears our artificial cells speak. So we’re just looking for a green-red cycle.

And so therefore it will be alive?

I absolutely would not say it’s alive. I would just say that we’ve mimicked one feature of life. Speaking of finding life on another planet, life is social. We will never find just one cell or one person on another planet, right? Life occurs in a community, and I think communication — coordinating group behavior — is fundamental to life.

I once worked with an artist named Sascha Pohflepp, and we discussed a lot of the differences between life and a machine. A machine keeps sort of chugging away, without worrying about its environment. But a living system has to. An automobile doesn’t care how much it pollutes the environment. A living system changes its environment, and the environment affects whether it’s going to live or die. You have to be able to sense and respond to your environment, and you can’t screw up the environment too much, or else you die.

So there is this communication aspect, whether it’s among cells, or between cells and the environment. And again, I think this is something that’s often ignored. But I think it’s a critical feature of life.

When you succeed in creating artificial life, you will let us know, right?

Of course.