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Princeton Powwow: RNA World's Last Hurrah?

PRINCETON POWWOW: RNA WORLD'S LAST HURRAH?

By Suzan Mazur

SARA IMARI
WALKER
SARA IMARI WALKER

"I think we need to move away from treating a strict RNA world scenario as the central accepted answer for the origin of life because most of the origin of life community don't think that's the definitive answer." -- Sara Imari Walker


Is next week's Origins of Life conference at Princeton University the RNA world's last hurrah? The Origin of Life community has largely rejected the RNA world, biochemist Pier Luigi Luisi recently describing it to me as a baseless fantasy. I asked physicist Sara Walker to weigh in. Walker is on the adjunct faculty at Arizona State University, a NASA postdoc fellow who is one of the presenters at the upcoming Princeton conference.

Long embraced by NASA despite decades of failed experiments, the RNA world is the organizing point for the Princeton gathering, which is co-sponsored by NASA. Walker acknowledges that the Origin of Life community does not think the RNA world is "the definitive answer." And NASA's award of $8 million in September of last year to Carl Woese et al. is proof that origin of life remains a largely philosophical discussion, with Woese telling me in October (sadly he died in December) that we don't know what life is, and that his grant to study the principles of the origin and evolution of life signalled that NASA is rethinking its approach to the origin of life problem.

Walker, who is a collaborator of ASU's Beyond Center director, Paul Davies, says she also finds inspiration in the work of Carl Woese and Nigel Goldenfeld regarding collective evolution and horizontal gene transfer along with the ideas of Stuart Kauffman and others on self-organization as an evolutionary process.

Her paper at Princeton is "The Algorithmic Origins of Life," co-authored by Davies.
Walker thinks "biological systems are dictated by the flow of information . . . how information is handled and processed can distinguish living from nonliving."

One of the interesting points of the Princeton conference is the attempt to open it up to parties beyond presenting scientists. A good thing. What's the big secret anyway? That the RNA world is a bust? That public money has been wasted?

The conference should be wide open to the public, held in a theater like the World Science Festival is, and streamed over the Internet. Public funding might then be a lot easier to come by for Origin of Life researchers.

Here's an internal email from the principal organizer of the Princeton conference, Laura Landweber, which I was able to access, discussing the possibilities of informing a wider audience.

"From: Laura Landweber lfl@princeton.edu
Date: December 29, 2012 9:35:25 AM EST
To: Recipient List Suppressed
Subject: remember to register for Origin of Life conference

If you plan on attending many of the origin of life talks the week of Jan. 21-24, then please register (which is free), because the room capacity is almost full, and then the meeting will be closed to registration (but we are working on webcasts, and there's also a video monitor outside the lecture room)".

Excerpts of my interview with Sara Walker follow.

Sara Walker has a BS in Physics from Florida Institute of Technology and a PhD in Physics and Astronomy from Dartmouth College. Prior to ASU, she was a postdoctoral fellow at NSF/NASA Center for Chemical Evolution at the Georgia Institute of Technology.

Some of Sara Walker's professional activities (present and past) include: Administrator, S.A.G.A.N. (Social Action for Grassroots Astrobiology Network); (and at Dartmouth College) Co-founder, Graduate Women in Science & Engineering; Co-organizer, Women in Science Mentoring Program; Community Service Award.

Suzan Mazur: It's good to see that about a third of the presenters are women at the Princeton Origins of Life conference next week, where you are a featured speaker as well.

Sara Walker: Yes.

Suzan Mazur: You were co-organizer of the Women Science Mentoring Program at Dartmouth a couple of years ago, which paired graduate women scientists with high school girls. Would you talk a little about the success of that mentoring program?

Sara Walker: It was indeed very successful. We took a group mentoring approach. A few graduate women in science met weekly with high school girls who had demonstrated a strong interest in science. It was so much fun. These girls lit up when we talked about dissecting frogs and things like that. It was not the kind of conversation they were used to having.

They also didn't really know what the college experience was like. We had an opportunity to walk them through it and introduce them to new ideas. It inspired me to see them inspired, so excited, wanting to know how to get into science while still in high school. Because when I was their age I wasn't sure what the world of science was all about.

Suzan Mazur: You're now collaborating with the esteemed Paul Davies, director of the Beyond Center at Arizona State University. Can you tell me when you first became interested in science?

Sara Walker: My interest in science began in high school but I didn't know what specifically I wanted to do in science. It was at Cape Cod Community College in Massachusetts, which I attended for two years, where I decided that I wanted to actually be a scientist. I took a physics class first term with Professor Shaw. I can still remember walking in to Prof. Shaw's class the first day and Prof. Shaw telling us about magnetic monopoles, these very illusive objects that had been predicted by theory but had never been identified in the laboratory. It was mindboggling to me. I was so excited about being enabled to then go out and look for these things.

After CCCC, I really wanted to be a physicist. I thought scientists who did theoretical physics, particle physics and cosmology were the absolute coolest people on the planet. I continued my undergraduate work at Florida Institute of Technology and then went to Dartmouth where I worked with Marcelo Gleiser.

Suzan Mazur: Marcelo Gleiser was your PhD advisor at Dartmouth, the Brazilian scientist, who is one of the participants at the upcoming Origin of Life meeting at CERN.

Sara Walker: Marcelo really got me interested in astrobiology and the origin of life. He told me that cosmology was cool but that he'd just started a project on origin of life and would I be interested in participating. I said sure.

Suzan Mazur: You've written a paper recently with Paul Davies called "The Algorithmic Origins of Life." Would you establish what you mean by an algorithm?

Sara Walker: An algorithm, in the context of the paper, is a program that allows the active use of information -- information processing -- which is really important to biological systems. It's not just that biological systems store their information in molecules like DNA, but that they actively use this information to operate.

Suzan Mazur: So the algorithm is a program that allows the active use of information. What about the information itself?

Sara Walker: Information can be loosely defined as events that affect and direct the state of a dynamic system. Saying that information is algorithmic really means that specific events are programmed to have specific outcomes in biological systems. So it's really the processing of the information that's unique about how biology operates.

Suzan Mazur: You say that at some point "information gains direct, and context-dependent causal efficacy over the matter it is instantiated in". What is the information you refer to?

Sara Walker: In this case it is the state of the system, an example the connections or topology of a biochemical network, so it is highly distributed. Function arises due to the distribution of information, therefore biologically meaningful information only arises in the context of the wider system.

Suzan Mazur: In your paper you discuss progress being made in understanding where and when origin of life happened. Other scientists I've interviewed differ. Gunter von Kiedrowski, for example, has told me the following: "We can't travel back in time, we'll never know the historical course [of the origin of life]." Steen Rasmussen told me essentially the same.

And Doron Lancet said this: "We will likely never know what were actually the exact chemical substances that began life. But we can wisely guess what principles such chemicals had to obey."

Would you comment?

Sara Walker: I do agree with those statements. The point is we've made a lot of progress looking at isolated parts of the problem. Identifying what some of the conditions on early Earth were and what you can synthesize under those conditions, what in biology seems to be essential molecules. But to move beyond that and prove an origins story, that's where you really need to get the deeper principles. The examples you gave from von Kiedrowski, Rasmussen and Lancet point to the fact that while we may never know the precise details of the chemistry or the exact sequence of events, we may still figure out the deeper principles at work.

Suzan Mazur: Doron Lancet also told me that we can't even say there were lipids way back when, that what existed might have been lipid-like. And he said it's also very assuming for us to be thinking that the way life is now with 20 amino acids and four nucleotides is "how life should have been from its inception" -- it could have been any set of molecules jump-starting life.

Sara Walker: I totally agree with that.

Suzan Mazur: So have we made progress on when and where it happened if we don't know what the chemicals were and it doesn't matter what the exact circumstances were? Lancet said further: " [I]f people tell you life began at a temperature of 25 degrees Centigrade, 110 degrees or 360 degrees (in suboceanic vents) -- this doesn't matter. What does matter, is the principle of what would constitute acceptable molecular roots of life, and at the same time have sufficient simplicity to warrant emergence from an abiotic mixture of chemicals."

Sara Walker: We don't even know which chemical systems came first. There's a huge debate between lipids or genetic polymers or peptides. We just don't know, and I agree the best way to find answers is to look at more general principles than precise chemical details.

Suzan Mazur: So all three questions are still up in the air -- when, where and how.

Sara Walker: Yes. We definitely are still up in the air in the origins of life investigation. But one of the reasons I'm optimistic about making headway in uncovering the deeper conceptual principles about origins of life -- the how -- is that scientists are understanding biology better. We're looking at things at a mechanistic level, observing biological systems operate, i.e., how protein networks function, etc. The problem is that we have to extrapolate from the chemistry and specific details of the life we know to try to figure out the more universal ideas that might be characteristic of any living system including those we haven't identified yet. That's really the hard part.

Suzan Mazur: Do you agree with the late Carl Woese that our Last Universal Common Ancestor was a process not something material?

Sara Walker: Yes. I'm a very big fan of Carl Woese's work. He's had a lot of brilliant insights into early evolution.

Suzan Mazur: It's very sad that he's gone, he had so much more to say.

Sara Walker: It is. I've been reading his recent papers. He's had amazing papers even within the last few years, not to mention over his whole career.

Suzan Mazur: Aside from being a great scientist, he was concerned about ethics in science and spoke his mind. He and Nigel Goldenfeld and colleagues had recently received an $8 million NAI grant to investigate the principles of the origin and evolution of life. He told me, that is the problem, we don't know what life is. How do you define life?

Sara Walker: I want to preface by saying that this is an incredibly hard question. And, you need to be careful, it can really bias your perspective depending on how you try and define life.

I have my own working definition that's based on how I approach origins of life, i.e., as a well-defined transition that might be characterized by informational principles. The short of it is that in living systems information has causal efficacy over the matter that it's instantiated in. And it's really this idea that biological systems are dictated by the flow of information. So the hypothesis is that how information is handled and processed can distinguish living from nonliving.

Suzan Mazur: What about the idea of not separating life and non-life? Maggie Turnbull, for example, says the Universe doesn't make the distinction between life and non-life. Carl Woese too talked about putting the organism back into its environment and connecting it to its evolutionary past to again feel "the complex flow." What are your thoughts about this?

Sara Walker: I agree on some level but I think the problem is that when a scientist is trying to work on the origin of life, it's not a well-defined question unless life is distinguished from non-life. Looking at the transition from non-living to living systems you have to define something changing. Therefore, I think it can be incredibly constructive to have conversations about what it is we are saying is changing because it helps in understanding what the processes are governing the emergence of life. It also helps to define what life is, i.e., what we are looking for when we go out to find it in the Universe.

Suzan Mazur: Pier Luigi Luisi recently told me the following: "The most popular view of Origin of Life by way of the RNA world, to me and to many others is and always has been a fantasy. . . . This is the story told to students and to me and is something without any scientific ground. . . Until somebody actually finds a way by which randomly produced RNA begins to self-replicate in not one single molecule but in a thermodynamically-driven process, the RNA world is baseless." Wouild you comment, particularly in light of the Princeton conference coming up, where the RNA world will be central to the discussion of origin of life?

Sara Walker: There's a lot of debate about it. The utility of the RNA world has always been that it's easy to study in the laboratory. It certainly seems that there was an early phase in evolution where RNA played a major role in the genetics system. But I don't think we can say anything beyond that. It seems very unrealistic to me that the early phases of evolution would have been dominated by RNA alone. I favor the ideas of self-organizing chemistry.

Suzan Mazur: Metabolism first?

Sara Walker: Yes. I like to think about life in terms of information flows and how information is being processed. And because information is so widely distributed in biological systems. I think there's merit to the idea of autocatalytic sets. Living systems are systems and we really need to have a systems approach to the origin of life. You can't just start with a single molecule. That's why I like the metabolism-first viewpoint because it really is about how systems act and evolve collectively.

Suzan Mazur: Are you referring to Stuart Kauffman's work with collectively autocatalytic sets (CAS)?

Sara Walker: Yes, his and the work of many others. I've also been intrigued by the work of Harold Morowitz and Eric Smith and others about the emergence of metabolism from the underlying geochemistry. I think these kinds of approaches have a lot of merit.

Suzan Mazur: There a widespread view in the scientific community that we're beating a dead horse with the RNA world. It hasn't worked. Stu Kauffman recently told me why he doesn't think an RNA world can work. Here's what he's written:

"With the discovery that RNA molecules could catalyze reactions, that is, ribozymes, many biologists became very enthusiastic that the same class of molecules, RNA, could both catalyze reactions and carry genetic information. This is much of what gave birth to the RNA World view of the origin of life. I find myself deeply puzzled by this, because RNA only carries genetic information via the protein enzymes which properly load each different transfer RNA. RNA carries NO genetic information by itself. So I don't see how an RNA world with only RNA can work. My own view is that collectively autocatalytic sets (CAS) in dividing compartments like lipid liposomes that bud, may be the most probable basis of the protocell able to evolve indefinitely."

Would you comment?

Sara Walker: I find it hard to envision how an RNA-only world wold operate. It is much easier to understand how a collectively autocatalytic system could have emerged and then acquired digital information storage through evolution toward refined and reliable information handling. Even in modern life, no individual molecular systems replicate independently without interacting with other cellular machinery -- cellular replication is a collective process.

So, I think we need to move away from treating a strict RNA world scenario as the central accepted answer for the origin of life because most of the origin of life community don't think that's the definitive answer.

Suzan Mazur: If the RNA world is the wrong approach, why are so many presenters at the Princeton conference speaking about the RNA world?

Sara Walker: The RNA world is where the experiments have been going on for a long time, and the experiments tell us a lot about molecular evolution. It still has a place in the scientific community

Suzan Mazur: How do you define evolution? You say "the concept of evolution itself may be in need of revision" and cite Carl Woese and Nigel Goldenfeld. What do you mean by evolution being in need of revision?

Sara Walker: I was thinking about Woese's idea about early life being dominated by horizontal gene transfer, and that life was more of a collective evolutionary process. It's much harder, however, to get your head around the concept of a loose collection, a network evolving. Conceptually, the RNA world is much easier because we can keep imposing the idea of the Darwinian paradigm of an RNA replicator with vertical descent..

Suzan Mazur: But you do think the concept of evolution is in need of revision.

Sara Walker: Yes. I think there are a lot of phenomena in evolution we haven't investigated in as much depth as the standard genetic evolution paradigm.

Suzan Mazur: Would you mention a few?

Sara Walker: Just from this conversation, Carl Woese and Nigel Goldenfeld's ideas about collective evolution and horizontal gene transfer. Stuart Kauffman's pioneering ideas of self-organization as an evolutionary process. The organization really driving it. These concepts are harder to define because they are not vertical.

More generally, in looking at living systems, one of the reasons they are extremely difficult for us to pin-down is that the information in the state of the system is a dynamical variable. You can't start with an initial condition and predict where the evolutionary trajectory will end up because the actual way it's changing with time is changing with the way that the system is changing.

Paul Davies and I talk about this. He likes to say that the "dynamical laws are changing with the state of the system" and vice versa, which is a good way to describe it. This is not something that we have a really good way of defining right now.

Suzan Mazur: You say there's a determining factor, it depends on the actual state of the system as to what happens in the future, but Kauffman says there's no entailing law. We can't know what's going to happen. Here's your statement: "it is the information that determines the current state and hence the dynamics (and therefore also the future state(s))".

Sara Walker: It depends on how far into the future you're predicting. It has a lot to do with conundrums introduced by self-reference. A great example is M.C. Escher's Drawing Hands, where one hand is drawing another and vice versa. It's difficult to tell what is the cause and what is the effect. Biology is much the same way, for example, we still have a lot of debate about which plays a more dominant role in evolution, genotype or phenotype. The point is that the operation of one subsystem is not well defined without the other, so you can't analyze it as a linear system.

So, I think it's difficult to predict. Kauffman goes so far as to say it would be impossible to predict because the evolution of the biosphere is not an algorithmic process. I can see that as a possibility but I'm not sure.

Suzan Mazur: Would you discuss the distinction between trivial and non-trivial replicators and say why you put lipid composomes in the trivial category when Doron Lancet et al. have shown success with lipid composomes with their GARD model, writing that "appreciable selection response was observed for a large portion of the networks simulated."

Sara Walker: Trivial replicators are perfectly capable of evolution. That's actually not the distinction we're trying to make. "Appreciable selection response" means it's an evolvable system.

Suzan Mazur: But you're saying no in the paper, you're putting lipid composomes in the trivial, not evolvable category.

Sara Walker: Trivial / non-trivial is not supposed to be a distinction about evolvable systems. That's one of the distinctions we're trying to make in the paper, that evolution may be necessary to life but it's not necessarily the defining feature.

The trivial/ non-trivial distinction is more about how information is handled and processed in that system. We look at trivial replicators as being systems that can replicate, but they can do so only within the specific confines of their environment and it's really dictated by their environment.

You could have an RNA sequence that could replicate, for example, but could only replicate with the right mixture of nucleotides under the perfect PH conditions, etc. You can contrast that with a living system which has some autonomy from the environment it's sprung from. It can reproduce because of the way it stores information in one place and processes it in another. So it's decoupled, the non-trivial flow of information in living systems gives them some autonomy.

We use von Neumann's example of the self-replicating machine as a simple framework for understanding this concept.

Suzan Mazur: But the von Neumann example, the Universal Constructor, is a machine not a biological system.

Sara Walker: But if you think about von Neumann's idea, the Universal Constructor, which is defined as a machine capable of building any machine in its environment given appropriate instructions including itself, it can provide some insight into how information flows in living systems. The UC requires information stored on a linear tape to tell it how to operate. That information is read out, and based on the instructions read out, specific tasks are executed. The task can include copying the machine.

Biology operates much the same way, except that the information is much more distributed. We like to think all information in biology is stored in DNA but it's much more complicated than that, how the information is read out also depends on the current state of the system, i.e., level of protein expression, environmental conditions, etc. So state of information is important too. The non-trivial information flow makes it a highly nonlinear system.

Suzan Mazur: So you think we need to be spending more time exploring the non-linear world?

Sara Walker: Yes. I do. I think we need to be exploring much more about how networks process information and how networks evolve and how self-referential systems operate.

Suzan Mazur: Would you like to make a final point?

Sara Walker: Yes. I'm incredibly optimistic about the origin of life investigation. We're understanding these complex issues more and more.

Suzan Mazur: Are you saying we're going to be able to travel back in time or that we're going to be able to make a protocell?

Sara Walker: Neither, but with regard to the protocell, I am hoping we will be making it soon. What I'm saying is that if we can understand the underlying physical principles governing how living systems emerge naturally, that's answering the ultimate question. It's more about the principles, what are the underlying mechanisms?

Suzan Mazur: What Carl Woese was looking at.

Sara Walker: Yes.

Suzan Mazur: I have one unrelated question.

Sara Walker: Sure.

Suzan Mazur: People are wondering what happened to Paul Davies' signature moustache, can you shed some light on the mystery?

Sara Walker: Oh Paul's moustache! It was right before I came to work for him that the moustache disappeared. I think he just got tired of maintaining it. Coincidentally, I had a recent conversation with Paul about going back to the moustache and he said it was just too much work.

********

Suzan Mazur is the author of The Altenberg 16: An Exposé of the Evolution Industry. Her interest in evolution began with a flight from Nairobi into Olduvai Gorge to interview the late paleoanthropologist Mary Leakey. Because of ideological struggles, the Kenyan-Tanzanian border was closed, and Leakey was the only reason authorities in Dar es Salaam agreed to give landing clearance. The meeting followed discovery by Leakey and her team of the 3.6 million-year-old hominid footprints at Laetoli. Suzan Mazur's reports have since appeared in the Financial Times, The Economist, Forbes, Newsday, Philadelphia Inquirer, Archaeology, Connoisseur, Omni and others, as well as on PBS, CBC and MBC. She has been a guest on McLaughlin, Charlie Rose and various Fox Television News programs. Email: sznmzr@aol.com

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