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Matt Powner: How to Make a Protocell

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Protocell pioneer Matthew Powner has the fresh-faced good looks of an athlete you'd expect to show up at World Cup 2014, and a voice somewhat reminiscent of the "British Invasion." (He's from the north of England.) But the relaxed focus he projects signals something profoundly more urgent: Matt Powner has the chemistry of the origins of life on his mind (though he says he actually does love to play a bit of football now and then).

Nobel laureate Jack Szostak, who recently told a World Science Festival audience that we'll have "life in the lab" in three years, once described Powner as "already a star" by the time he arrived as a postdoc at his Harvard lab five years ago, because Powner, as a Ph.D. candidate at the University of Manchester, and John Sutherland, then his advisor, were able to find a way to synthesize two of the four nucleotides of RNA: uridine and cytidine. Szostak considers this one of the pivotal events in origin-of-life research, and indeed, a crucial part of what remains to be done to meet Szostak's announced three-year deadline depends on the creative chemistry of John Sutherland and Matthew Powner.

In 2012 Sutherland and Powner teamed up to win Harry Lonsdale's Origin of Life Challenge and $50,000, plus $150,000 in research funding. Powner has now established his own lab at University College London, where he continues his origins investigations. Sutherland works from the University of Cambridge.

Aside from renewed funding in 2013 from Lonsdale, Powner and Sutherland are now also being supported as investigators at the Simons Foundation Origins Collaboration, headed by Harvard astrophysicist Dimitar Sasselov and Jack Szostak.

Matt Powner's B.A., M.S., and Ph.D. in chemistry are from the University of Manchester.

He is the recipient of numerous honors and awards, including the Lonsdale Origin of Life Challenge shared by John Sutherland; the Roscoe Medal (Science Engineering and Technology for Britain); the Stanley Miller Early Career Research Award (International Society for the Study of the Origins of Life); the Royal Society of Chemistry Prize (University of Manchester); the Swan Prize (U. Manchester); the Merck Sharp and Dohme Award (U. Manchester); and others.

I met Matthew Power recently at the Simons Foundation in New York. Our interview follows.

Suzan Mazur: Were you at all divided in your career choice in science? Was there something else that you were considering?

Matt Powner: When I left undergraduate study, I first interned at AstraZeneca. I thought my career in science meant making drugs, working for a pharmaceutical company, because I had this passion for organic chemistry and building molecules. But following the AstraZeneca internship, I decided I wanted a Ph.D. before actually working in Pharma. While looking for a Ph.D., I found John Sutherland and made a U turn into origins-of-life research.

As an organic chemist, investigating origins seemed valuable, intellectual, something I really wanted to put my time to for three years or so. From that point on there's been no other course I've really thought about pursuing.

Suzan Mazur: How far back does your passion for science go?

Matt Powner: I don't think I was sciencey at school. I was just quite good at it.

Suzan Mazur: Did you have parallel interests? Music? Acting? The arts?

Matt Powner: Sports. I did a vast amount of karate as a kid. And other sports. Football.

Suzan Mazur: Acting?

Matt Powner: No. Science just really made sense to me. I'm not sure where it comes from -- good teachers and perhaps the way I interacted with my parents. The sciences just appealed to me. All of them: physics, chemistry, biology. I could get along with those subjects more so than the arts.

Suzan Mazur: You have an interesting accent.

Matt Powner: I come from the north of England.

Suzan Mazur: Do you come from a science family?

Matt Powner: Not really. Dad has been a farmer and a plumber and electrician. Mom's background is banking -- math-related but not science.

Suzan Mazur: Were you always a scholar?

Matt Powner: I always did very badly at school until nearly the end of high school. In fact, I had a chemistry teacher who told me chemistry just wasn't the subject for me.

Suzan Mazur: I first learned of your work on the origin of life two years ago when you and John Sutherland won Harry Lonsdale's research prize. Would you highlight what your original proposal was and where you are now with that Lonsdale-funded research?

Matt Powner: In 2011 John and I published a paper suggesting that in a search for a global system that could be geologically plausible, that could give rise to multiple systems essential to life, we should couple chemical research and the investigation of chemical systems.

We used the example of nucleotides and lipids. Our thinking was that if we could find multiple systems to cross-reference chemically so that one type of chemistry could give rise to both those classes of molecules, we could use that to infer what geochemistry was at life's origin.

Our proposal was to use chemistry to define geochemistry rather than the usual origins-research approach of beginning with a model of geochemistry to define the parameters of the chemistry.

Suzan Mazur: Where would you say you are now in your research on this?

Matt Powner: Funding to our labs by Harry was renewed last year at the same level based on peer review by Ram Krishnamurthy, Jack Szostak, Irene Chen and Nicholas Hud. John Sutherland's lab is at Cambridge, and my lab is at University College London.

We've submitted a one-year report to Harry Lonsdale and his reviewers, and we gave an online seminar. They were happy we'd made progress. We are about to give our second-year report.

Funding was also renewed at the same level to the other researchers originally awarded grants by Harry: Niles Lehman, Peter Unrau and Paul Higgs, and David Deamer's team, Wenonah Vercoutere and Veronica DeGuzman.

Suzan Mazur: Can you talk a little about the results?

Matt Powner: I do think we've made a lot of progress over the last two years. Some of the work, specifically from John pushing this, is looking at copper cyanide chemistry and reduction of simple molecules, reduction into cyanide to give sugars, so linking chemical systems to photochemistry, which really kind of resembles the way biology operates now.

Suzan Mazur: Is the Lonsdale funding to support your research and John Sutherland's research in general, or is this a separate project that's being funded?

Matt Powner: It's in general. It's specific to our labs.

Suzan Mazur: Is that the same situation with the Simons Foundation funding you and John Sutherland are receiving? Simons is supporting your research in general?

Matt Powner: Exactly. The Simons Foundation supports the lab and research program of each investigator, as well as specific research proposals of each of its postdocs.

The Harry Lonsdale money, which is great, supports half a studentship -- half the cost of one Ph.D. student for my lab.

Suzan Mazur: I know the Simons Foundation postdocs are being funded at $50,000, plus another $30,000 for health insurance, travel and supplies. Are the investigators receiving a larger sum?

Matt Powner: The investigators get different sums depending on how senior they are.

Suzan Mazur: The origins research is being done in labs outside the Simons Foundation in all cases?

Matt Powner: Yes, I'm pretty confident that it's all outside the foundation.
I think the biggest strength of the Simons Foundation Origins Collaboration is that the group is really broad. This inspires people to think outside the box about everything from astrophysics -- with people like Dimitar Sasselov involved -- from planets, stars, galaxies, right down to single molecules and how they work, to the atomic scale and everything in between.

Suzan Mazur: I interrupted your research description.

Matt Powner: Part of our research relates to the making of very simple molecules, taking hydrogen cyanide and building more complex two- and three-carbon species. Another aspect is looking at the next level of complexity: how we can build a nucleotide, something that's significantly more complex, although it's a long way from a biological species; how to build bigger macromolecules from that. We're doing quite well, I think, on all fronts.

Suzan Mazur: Do you define your work as making a protocell, or are you exploring how it could be made? What is the goal?

Matt Powner: We're interested in aspects of development all the way to a protocell. We're a smaller, younger lab than John's lab. At the moment our focus is molecular compositions, an earlier stage. We're looking at core components of biology and why they may have formed the specific way they have and how that can be controlled by chemistry.

Suzan Mazur: The end goal is to make a protocell?

Matt Powner: Partly. My end goal isn't just to make a protocell. You could make a protocell any way you want to. You can manipulate all the parts. None of it could look biological. You could make membranes of non-biological polymers. You could have non-biological information transfer. You could have something resembling metabolism that looks nothing like biology, and that will tell you a lot about assembling something that can act and look like a cell.

The focus in my lab now is understanding why biology took the route it did. Biology has assembled a specific set of components. We want to shed light on why those specific components, through the rules of chemistry.

Suzan Mazur: A protocell can be built at this point, but not one that can self-reproduce.

Matt Powner: Some labs would say they can build a protocell. But yes, getting biological, tight, self-sustained replication is [down the road].

Suzan Mazur: Is John Sutherland's lab more aggressively pursuing the making of a protocell?

Matt Powner: I guess you should ask John.

Suzan Mazur: Well, his work has been described as "research to discover systems chemistry, the syntheses of the informational, catalytic, compartment-forming molecules thought necessary for the emergence of life."

Matt Powner: Yes.

Suzan Mazur: Sounds like protocell development.

Matt Powner: To me it sounds like he's trying to understand the chemistry that can assemble the parts you need for a protocell.

Suzan Mazur: And then you can make one?

Matt Powner: Information of how you assemble those into a protocell is not clear. Whether John's lab is currently looking at the assembly of those systems, which they could well be, you need to really ask John.

Suzan Mazur: Prior to your winning the Lonsdale Origin of Life Challenge, I understand you were a postdoc in Jack Szostak's lab in the U.S. Were you working on protocell development there? What can you say about your experience in the Szostak lab?

Matt Powner: I worked more on the genetics side in Jack's lab. I was there for just over two years, 2009 to 2011. I started at University College London in 2012.

Jack's lab at that time had largely two aspects. One side researched protocells, lipids, assembly, growth and division of vesicles. I worked on the other side of the lab, the genetics side, where the focus was genetic molecules, genetic polymers. We played more with RNA, the natural component. We also moved a little bit away from RNA and explored non-natural genetic polymers.

Suzan Mazur: How would you rate your experience there?

Matt Powner: The Szostak lab was a really free-thinking place, great to work in. Lots of bright people to sit and talk with. Lots of freedom to explore my own ideas as well.

Suzan Mazur: How much of your work there was experimental, and how much was computer simulation?

Matt Powner: It was 100-percent experimental.

Suzan Mazur: What about your work now?

Matt Powner: Same thing. One-hundred-percent experimental. We only use computers to draw pictures of what we did in experiments. Powerpoint and Word is about all we use computers for.

Suzan Mazur: Jack Szostak has commented that you were already "a star" and "incredibly focused" when you came to his lab as a postdoc because of your work on synthesizing nucleotides with John Sutherland. Can you tell me about the nucleotides work and also your research on purines as building blocks of DNA and RNA?

Matt Powner: My initial project when I joined John's lab was to look at TNA.

It was one of Albert Eschenmoser's ideas for non-natural, non-endogenous nucleotides to propagate information that may have been important in the early stages of life. During an in-depth discussion with John, John and I decided to remodel my project to attack the problem of ribonucleotides.

RNA is a cornerstone of modern biology, a cornerstone of genetics, inheritance, and evolution. We weren't willing to accept that RNA was inaccessible at the dawn of evolution. It seemed so important to us, yet synthesis was still a huge stumbling block for RNA, something scientists essentially agreed was critical at some early stage in evolution.

So I started thinking about what was known about nucleotides and what the best routes out there were and how we could change them, come at them from a slightly different angle.

John and I used as a starting point some of the vast amounts of work done by Leslie Orgel and colleagues, and without Orgel's previous work what we did would have been infinitely more difficult.

What we were able to find, without getting too technical, is that by slightly changing the conditions, by building our molecules in a slightly different order -- the order in which we made the bond in the final nucleotide product -- we could come by really robust and high-yielding synthesis in two of the four nucleotides, uridine and cytidine.

That was important in reinvigorating RNA as not the only player in town but as a really important part of biology. Those syntheses suggest that it may have been possible that it was a really important molecule in the first biology. The control of chemistry could allow you to synthesize at least those two components of RNA, and we'll get to the purines as well, and maybe DNA. So we found that the specifics of fairly simple chemical reactions could in a controlled manner give these two nucleotides.

So there's always been lots of very intriguing chemistry, catalysis, etc., that relates to large pieces of RNA, but the real stumbling block was how to get the original monomers that you can synthesize, long pieces of RNA that can then interact.

I'm not necessarily saying you have to have monomer-by-monomer synthesis of RNA, but to make RNA you're going to have to make a pool of nucleotides.

Suzan Mazur: Can you discuss what's missing from the mix at this point? What are the outstanding issues in creating a self-reproducing protocell?

Matt Powner: We'll need 10 to 20 years to make the kind of protocell that actually progresses toward biology, one that could be described as a missing link between prebiotic chemistry and what we now know as life. That is in some ways distinct from just any protocell.

You could envisage lots of variable components of a protocell that relate in no way to biology -- subsystems of a protocell, such as membranes, for example. But what's missing for me are the interactions between the components, like how you get a hereditary molecule to interact with the membrane-forming molecule so those start down the path toward coupled evolution -- beyond assembly -- understanding how the system could self-assemble from chemistry.

Much more needs to be understood, like coming up with a reasonable purine synthesis. A lot of this relates to building bigger and bigger systems, bringing together multiple aspects of molecular entities and getting them to interact in a way that's productive.

Suzan Mazur: Is autocatalytic sets a somewhat marginalized approach at this point in protocell development?

Matt Powner: I don't think the idea of autocatalytic sets has been marginalized, but I don't know if it's necessary. My understanding of the concept is that autocatalytic sets can in essence themselves evolve purely through change in chemical composition. I'm not sure that's been demonstrated in a relevant system that doesn't rapidly degenerate, and I'm not sure that's the essential step to building what we know as a modern cell. However, if we actually found that autocatalytic sets work, this could be a lynchpin to understanding origin of life.

People should research what they think is important. Scientists will think different things are important, and that's good. You don't want everybody to focus on the same question or part of the question. What we will almost certainly come to realize in the fullness of time is that everyone was at least in part wrong but multiple theories were in some small part right. Without a crystal ball the only way to move things forward is through empirical evidence.

Suzan Mazur: Why build a protocell in the first place? I think you told me when we met at the Simons Foundation that it was largely sort of getting to the bottom of things, that the puzzle was intriguing.

Matt Powner: Yes. We're fundamentally interested in the scientific question: Why is nature the way it is?

Suzan Mazur: And beyond that, no one knows until it's made what the applications could be?

Matt Powner: From that technology can flow. But none of it means anything until we know the results. What it now requires is getting self-assembly at this level to occur.

But you never know what blue-skies research is going to turn up. And the increasing emphasis on systems chemistry could be hugely advantageous for reinvigorating the whole field of chemistry as well as the economy.

Suzan Mazur: There are some grumblings that it's one of NASA's missions to control origins-of-life research. Would you comment?

Matt Powner: As someone who's never been involved with NASA, I don't feel restricted by what NASA does or by what NASA says. I don't feel that NASA is controlling origins-of-life research, and I don't think they should. I'm not sure to what end they would want to either.

Suzan Mazur: What about the European space program? Is there a NASA counterpart there on origin-of-life research?

Matt Powner: No, there's no European Space Agency exobiology space program like NASA has.

Suzan Mazur: Why do you think that is?

Matt Powner: Level of funding.

Suzan Mazur: Origin of life is funded in a different way in Europe?

Matt Powner: Yes. Just my guess.

Suzan Mazur: Are you in favor of more public funding and more public awareness regarding origin-of-life research, or do you think the subject is too esoteric?

Matt Powner: Origin of life is a problem no one knows the answer to. But we can formulate a concept of a sterile planet. We can formulate a concept of a biosphere. Anyone can do both of those things. What links those two and how we could move from one to the other is hugely interesting.

I think the public wants to know what's happening with origin-of-life developments and should know. It is something that increasingly inspires people in science, and it is rare in terms of projects where chemistry can have a large input.

Where we came from is a fundamental question, compelling for everyone irrespective of background. I think there should be more public awareness of developments, and increased public funding could actually follow. But this is a loaded question for someone in the field.