Podcast Transcription

Steve: Welcome to a special edition of Science Talk, the weekly podcast of Scientific American posted on October 5th, 2009. I am Steve Mirsky. In this episode, we'll replay an interview with Harvard Medical School biologist Jack Szostak. Very early this morning Szostak was informed he had shared the 2009 Nobel Prize in Physiology or Medicine. We will also play a telephone interview conducted by Scientific American editor George Musser with Jonathan Mostow, director of the new Bruce Willis sci-fi thriller, Surrogates. To let you know about Jack Szostak, here's today's 60-Second Science daily podcast about the Nobel Prize:

Voice: The 2009 Nobel Prize in Physiology or Medicine goes to Harvard's Jack Szostak, Johns Hopkins's Carol Greider and Elizabeth Blackburn at U.C. San Francisco for their work on how chromosomes are protected by telomeres and the enzyme telomerase.

The Nobel laureates' research helped explain how an organism's DNA is successfully copied when cells divide. Telomeres are genetic sequences that act like little protective caps at the end of chromosomes—think of the sealed tips of your shoelaces. Telomerase is the enzyme that builds telomeres.

Blackburn and Szostak determined that it was a specific DNA sequence in the telomeres that kept chromosomes from fraying whenever they were copied when a cell splits in two. Blackburn and Greider discovered telomerase. The findings have implications for the understanding of aging and cancer. Because if the enzyme keeps the telomeres robust, the chromosomes stay protected and the cell's aging is slowed. And in cancer cells, which unfortunately do not seem to age, telomere length is maintained virtually indefinitely. Szostak, Greider and Blackburn thus revealed one of life's basic mechanisms, and paved the way for new medical strategies.

Steve: In May 2008 I attended an evolution conference at Rockefeller University here in New York, where I met Jack Szostak. His more recent work is on the origins of life.

Steve: What exactly does somebody who is studying origins of life do that a regular old evolutionary biologist doesn't do when they are doing their research?

Szostak: Well, [what] we are really trying to understand is how molecules can get together and start to act in a Darwinian fashion. So we are talking about the origin of cellular systems that can evolve, which is completely different from the way that chemicals interact with each other.

Steve: How is it different?

Szostak: Well, chemical reactions are, you know, controlled by the thermodynamics of chemistry, by kinetic considerations; but Darwinian evolution is completely different because, in our case, we are talking about populations with variation and the selection of variants that are more fit, and [as] that is repeated and repeated, then the better variants come to dominate the population. You just don't have that kind of cyclic feedback system in a simple chemical reaction.

Steve: So, where are we in this kind of research? I mean, obviously no one has created a living cell from buying reagent grade chemicals, so where does the research stand right now?

Szostak: Well, that's basically what we're trying to do, but it is obviously going to be a long process. The way we're thinking about it, the critical components that we have to think about, are some kind of genetic material. So it could be RNA or DNA like we have in modern biology or it could be some related kind of material; and we are also thinking about some kind of cell envelope, [a] cell membrane. Not that that's necessarily the very first way Darwinian systems began, but at some point they had to transition into a system more related to modern biology where cells are all bounded by membranes. So we're thinking about how to assemble these two components and get them to interact with each other.

Steve: That's an important point—should you succeed, that doesn't necessarily mean that that's the way it happened, it's just a, sort of, a proof of concept, right?

Szostak: Absolutely! I mean what we're interested in is figuring out plausible pathways for the origin of life. It would be great to have even one complete plausible pathway, but what we find often is when we figure out how one little step might have worked, it gives us ideas, and then we end up with ultimately two or three or more different ways in which a particular step could have happened. So that makes us think the overall process might be more robust. So, you know, ultimately it would be nice, I think, if it turned out that there were multiple plausible pathways; then, of course, we might never know what really happened on the early Earth.

Steve: And it should also be noted that this is a pretty young field, so it's—some people who don't want you to succeed point out that no scientist has been able to pull this off yet, but it's not really surprising. It is a complicated thing and people haven't been working on it all that long.

Szostak: Yeah, I think, you know, in some ways the field can be dated to the, you know, early experiments of Stanley Miller about 50 years ago. So it's a long process going from very small, simple molecules up to a cellular structure. There are parts of a pathway that I think are getting to be well understood, but there are many gaps in our understanding. But just because there are parts that we don't understand doesn't mean that we will never understand.

Steve: You gave a talk yesterday. You talked about some of the simple and yet unexpected phenomena that you see as you are doing this research. Can you talk a little bit about that?

Szostak: Yeah, sure. I think one of the interesting things about approaching this problem—they are actually trying to a build system—is that you come across all kinds of unexpected interesting phenomena. And I think it is really nice, a sort of, broadening our perspective, making us think about different simple, physical processes, different things that membranes can do, different ways, you know, the environment can impact the assembly processes. There's a lot of surprising stuff out there once you really start to investigate the system in detail.

Steve: Can you talk about any other specifics there?

Szostak: Well, I can mention some of the things that have been published. For example, a few years ago, we were starting to look at the way that membranes self-assemble—and these are not modern kinds of membranes, these are membranes made with fatty acids. And it turns out that the assembly of membranes is actually catalyzed by preformed membranes—that's the surface phenomenon, and it is generalized, and many different surfaces will catalyze membrane assembly. And one of the interesting ones is that clay minerals will help membranes to assemble; so it turns out there is a very common clay mineral that had previously been looked at by prebiotic chemists and shown to help RNA molecules to assemble. So ultimately what we had was a simple common mineral that can help genetic material to assemble, can help membranes to assemble, and it turned out can help bring them together. So that was a very satisfying outcome. But, you know, it has turned out there are many other unanticipated simple physical processes that have been found in the course of these kinds of experiments as well. Well, one of the issues that we have to think about is how small molecules can get across membranes without all the complicated modern biological machinery that controls the transport of molecules across membranes. So, we were starting to look at how simple molecules like sugars get across these fatty acid membranes, you know, spontaneously without any help from fancy proteins—and it turned out completely unexpectedly that ribose, which is one of the building blocks of RNA, gets across a wide range of membranes much more quickly than a set of very closely related sugars. So it makes you think that, well, maybe that could have been one contributing factor to why we actually use genetic materials that incorporate ribose, because early cells that relied on an external source of ribose would have had easier access to that material compared to competing the cells that we're looking for, a different sugar that had a harder time getting across the membrane. Now we still don't really understand why ribose gets across so much faster; we have some ideas but that's just a topic that's going to take a lot more study, but we never would have found this surprising result, you know, if we weren't systematically looking at these kinds of transport processes.

Steve: So if you want to make new RNA, if you are duplicating RNA within that membrane, the fact that you can bring ribose into the protocell easily is a real advantage there?

Szostak: Yeah, that would become an advantage at the point where the early steps of metabolism started to evolve.

Steve: So where do you think you're going to be in—or the whole field is going to be in—you know, this is the typical hackney journalist question, but where do you see yourself in 10 years?

Szostak: Well, the progress over the last 10 or 20 years has been on the one hand very encouraging, right—we have learned a tremendous amount. On the other hand we have also learned that there are things we don't understand that we hadn't even thought about before. So, you know, I can't really say that we will have built a cell in three years or 10 years or 20 years, and we don't even know all the problems yet. But I think the relevant part is that there are lot of really interesting scientific questions that are easy to investigate; there is a lot of interesting stuff that we are going to find out. So I think it is just going to continue to be an exciting time.

Steve: What's one of the things that you didn't realize you'd need to know that you now know that you need to know?

Szostak: Well, it's looking like one of the aspects that may take us some time to figure out is how to get a self-replicating genetic system off the ground. And when I started off in this field about 20 years ago, I was pretty confident that it would be something we could do relatively easily [with an] RNA catalyzed replication system, and that's turned out to be substantially more difficult than I thought.

Steve: Where RNA pretty much catalyzes its own reproduction?

Szostak: Right. So there has been tremendous progress in that; we have, sort of, proof of principle. Ribosomes that are RNA-dependent, RNA polymerases, which is great, but I think we really have to step back and think about the problem in a different way in order to develop a simple, effective system that can actually do self-replication and not just be a proof of principle. So that has made us look again at the chemistry of replication and start to explore a wider range of nucleic acids.

Steve: Jack Szostak had an article in the September issue of Scientific American called "The Origin of Life on Earth"—it's available at our Web site. His co–Nobel laureates, Elizabeth Blackburn and Carol Greider, coauthored a February 1996 Scientific American article called "Telomeres, Telomerase and Cancer" and we have re-posted that on our Web site. You can access both articles free for a limited time.

(excerpt from the trailer)

Voice: Robotic human surrogates combine the durability of a machine with the grace and beauty of the human body. With most people living their lives through their surrogate selves, our world has become a safer place. Take a seat in your stem chair and just with the power of your mind, you can control your surrogate, and send it out into the real world. You see what they see, feel what they feel, and become anyone you want to be from the comfort and safety of your own home. You can finally live the life you've always dreamed of without any risk or danger to yourself.

Voice: We are confronted with an unprecedented situation. Two people have died while connected to their surrogates.

Voice: I think we may actually have a homicide here.

Voice: The public cannot be allowed to get the idea that using a surrogate can be fatal.

Voice: Especially if it's true!

Steve: That's from the trailer for the new Bruce Willis sci-fi thriller, Surrogates. Scientific American editor George Musser recently spoke to Surrogates director, Jonathan Mostow.

Musser: I just wanted to [ask] your thoughts on some of the sociological and kind of social-technical, technological themes of the film as you see them. What are the things you're really trying to bring out with this project?

Mostow: Well, it is, you know, there's an old saying: If you want to send a message use a telegram. I think it's always dangerous if you set out to make a movie for the purpose of expressing a message. I think that you have a lot better luck when you're drawn to a story [with an] idea that resonates with you on some level that maybe at first you can't even articulate for yourself, and then as you immerse yourself more in it, you realize that even [if] it spoke to you on some level—the reason it [compelled] you is that it's speaking the truth to you about something in your own life or in society's current situation that feels truthful and feels like you are able to explore an idea or express an idea that in another [movie] might not be so well suited for. So in the case of this movie, well this movie winds up doing is actually asking a question, and the question it asks is what price do we pay for having all this wonderful technology that we are, you know, using—and you know, I love my computer, I love using e-mail and, you know, [Facebook and] Twitter and all these innovations, [they're] fantastic; and yet you can easily find yourself stuck into this and actually you're spending hours a day staring at a computer screen—and [yet] every moment that you spend doing that is a moment you are not with your family, with your friends, going out for a walk, doing something real in a real world. So it is a situation where, you know, we're all more connected to each other than we've ever been in the history of our species and yet [you] can also make the argument that we're, sort of, more disconnected from each other than ever before, because we interact with each other only virtually, not in person.

Musser: It's ironic—that seems to be a condition of the modern era, where connectivity goes hand in hand with [dis]connectivity; and we've had that, I mean, we don't live in villages anymore, we are in cities, we have more people around than ever before and yet we feel more distant from them.

Mostow: Yeah, I mean, I believe that 1,000 years from now, historians will look back at the time we are living in right now, and in distance like this, this decade or maybe even these couple of years as a turning point in the history of mankind; not [unlike the way] we look back on primitive man, when they discovered fire and how that world is changing society. You know, at the time that they discovered fire I am sure they thought, [Oh, this is great; we don't have to eat raw animals anymore [and] we can heat our caves. And yet the discovery of fire led to many different things, literally in how we live and how we interact with each other, you know, it's meant that people can stay up later, you know, and live in places they couldn't otherwise [live in] and, you know, [I'm only] scratching the surface of what the implications of it are. But in the same way what is it doing to us that we are spending all this time and all this energy interacting with each other through all these electronic means—and I don't know the answer and the movie doesn't try to provide the answer. The movie only simply, welcomingly asks you this question, yes, in the context of a Hollywood, you know, action thriller.

Musser: So, it was really seeing those kinds of themes in your own life, the elements of the story, in your own life that drew you to this particular one?

Mostow: I read, I mean, for me this project began with reading a graphic novel and, you know, it was sent to me with the question of do I want to develop this into a movie? And, you know, I get a lot of stuff sent to me for the purpose of turning [it] into movie and almost all [of it] I say no [to], because [there's] not fundamentally an [interesting] idea at the core of it. You know, I just, if you would need to do a movie, you have to be prepared to spend two years of your life, doing [nothing but] thinking about that movie, that idea. So if there's not something compelling there, [it's a] pretty empty exercise to go through. So in the case of this movie, I read the graphic novel, and I thought, "Wow—this is such a simple idea [really]." It's just the idea [that everybody] stays at home and lives their life vicariously [through these] remotely operated robots. And yet it spoke to exactly how I think I am running my life to a great extent and how our society is going and so it leads to your thinking about the societal impact of how technology affects us, but also the individual psychological way that it's affecting us.

Musser: How about some of the specific kind[s] of technological themes; how much did you really want to push people's visions of robotics or what would happen to the computers in the future as opposed to some of the social questions?

Mostow: Well, one of decisions I made early on was to not set the movie in the future. That's actually a big difference [from] the graphic novel. The graphic novel is set, I think, in the year 2054. And I started out doing that and I realized, "You know what? We're going to spend all our energy [designing] flying cars and futuristic telephones and all these things, and it doesn't have anything to do with our story." The fact of the matter is this technology that's in the movie, although doesn't exist yet, from [the standpoint] of what it represents, it actually exists. [The idea that you can] pretty [much] function by never having to [leave] your house; that's [the here and] now already. So I just started that we would set this world, this movie, in a world that looks like today [with] the only difference being that, you know, it is populated with these surrogate robots. And it was also, I [was also helped in] that choice by looking at a lot of movies that had been done in the future, and at some level, they kind of all fall short because something about them ultimately feels vague, and you are distracted by looking at a car that's going to be the futuristic car, [and you're thinking, Is that how] cars [are] really [going to be?] So we just think like in a movie, we see somebody who is going down the street and you see just a telephone booth that you are passing and you realize, well that's [not] actually a telephone booth, that's some sort of charging apparatus where people need to charge the surrogates and basically just kind of dock themselves into these charging [bays] and, you know, charging up for half an hour there to refresh the batteries before they have to continue to move on with the day.

Musser: Have you spent time yourself on things like Second Life and some of these immersive realities?

Mostow: You know, I don't have the time. I know I['d] just spend three hours a day [doing that], so I, you know, check myself.

Musser: [Does that come out in] the film? [Are there a] lot of people who have kind of self-corrected, and they're realizing, "Oh! I am spending too much time on this, in my virtual world, I should do something else"?

Mostow: No, but purposefully not; that there is two kinds of people [in this movie:] the people who are basically, you know, using this technology, which means you are basically using it all [the] time; or people who would have just outright rejected it and don't want to live in a world where people are living like this, and [the movie] make[s a very] clear distinction between those two groups of people. You know, it's interesting because the graphic novelist [based] his graphic novel, the inspiration of [it is] what I should say, where he read some academic writing of a guy that has done studies on people that were just [addicted to] the Internet, just could not [unplug from their] computers. And the interesting thing is that research was done in mid-1990s, which to us now is like the dinosaur age of computers. You know, back then most of us had dial-up modems, there was no Facebook, there was no Twitter—these things were all very primitive. And yet already there were people at that point that just couldn't get themselves to get up out of their chair and leave their computers.

Steve: Check out George Musser's September 24th blog item about the movie Surrogates at www.ScientificAmerican.com/blog and go to the Web site for the latest science news including our breaking coverage of the Nobel Prizes all this week. You can also follow us on Twitter: The handle is "at SciAm"—that's S-C-I-A-M—and my own tweets are available at "Steve Mirsky". This has been Science Talk, the podcast of Scientific American. Thanks for clicking on us.

Related Video: Ribosome Revelations: A Conversation with Nobelist Venkatraman Ramakrishnan

Jack Szostak, who just shared the 2009 Nobel Prize in Physiology or Medicine, talks about his latest research on the origin of life. And Scientific American editor George Musser talks to Jonathan Mostow, director of the new Bruce Willis sci-fi thriller Surrogates. Web sites related to this episode include www.snipurl.com/surrogates; www.snipurl.com/telomere; www.snipurl.com/origin