Robert Shapiro—LIFE: WHAT A CONCEPT!

Robert Shapiro—LIFE: WHAT A CONCEPT!

An Edge Special Event at Eastover Farm
Robert Shapiro [5.9.07]

"Life/ Consists of propositions about life." — Wallace Stevens("Men Made out of Words")

I looked at the papers published on the origin of life and decided that it was absurd that the thought of nature of its own volition putting together a DNA or an RNA molecule was unbelievable.

I'm always running out of metaphors to try and explain what the difficulty is. But suppose you took Scrabble sets, or any word game sets, blocks with letters, containing every language on Earth, and you heap them together and you then took a scoop and you scooped into that heap, and you flung it out on the lawn there, and the letters fell into a line which contained the words “To be or not to be, that is the question,” that is roughly the odds of an RNA molecule, given no feedback — and there would be no feedback, because it wouldn't be functional until it attained a certain length and could copy itself — appearing on the Earth.

ROBERT SHAPIRO is professor emeritus of chemistry and senior research scientist at New York University. He has written four books for the general public: Life Beyond Earth (with Gerald Feinberg); Origins, a Skeptic's Guide to the Creation of Life on Earth; The Human Blueprint (on the effort to read the human genome); and Planetary Dreams (on the search for life in our Solar System).


ROBERT SHAPIRO: I was originally an organic chemist — perhaps the only one of the six of us — and worked in the field of organic synthesis, and then I got my PhD, which was in 1959, believe it or not. I had realized that there was a lot of action in Cambridge, England, which was basically organic chemistry, and I went to work with a gentleman named Alexander Todd, promoted eventually to Lord Todd, and I published one paper with him, which was the closest I ever got to the Lord. I then spent decades running a laboratory in DNA chemistry, and so many people were working on DNA synthesis — which has been put to good use as you can see — that I decided to do the opposite, and studied the chemistry of how DNA could be kicked to Hell by environmental agents. Among the most lethal environmental agents I discovered for DNA — pardon me, I'm about to imbibe it — was water. Because water does nasty things to DNA. For example, there's a process I heard you mention called DNA animation, where it kicks off part of the coding part of DNA from the units — that was discovered in my laboratory.

Another thing water does is help the information units fall off of DNA, which is called depurination and ought to apply only one of the subunits — but works under physiological conditions for the pyrimidines as well, and I helped elaborate the mechanism by which water helped destroy that part of DNA structure. I realized what a fragile and vulnerable molecule it was, even if was the center of Earth life. After water, or competing with water, the other thing that really does damage to DNA, that is very much the center of hot research now — again I can't tell you to stop using it — is oxygen. If you don't drink the water and don't breathe the air, as Tom Lehrer used to say, and you should be perfectly safe.

However, around the year 1980 a physicist friend, Gerald Feinberg, now deceased, needed an organic or biochemist to collaborate with on the book he wanted to write called "Life Beyond Earth," which was based on his conception of physical principles. And he loved to think in exotic terms. One of his favorite inventions was a particle he named the tachyon.

Now it's known that there's a barrier at the speed of light, and something that's moving slower than the speed of life can't exceed it, but he conceived of a particle that's moving faster than the speed of light and can't slow down to the speed of light. Something like the bus in the movie "Speed." Except that was about 59 miles an hour, which is a little slower than light.

He named that the tachyon, and that was part of his claim to fame. He had quite an imagination, and by contact with him I developed an imagination too and we began to think, what is there that's special about life, that binds it not only to DNA and RNA and proteins, but to even carbon chemistry, or, in his mind, and I'm not prepared to speak on his topics, to chemistry at all.

In this book he liked to fancy life and liquid helium, plasma life in the center of the sun, laser life, which is all energy and didn't depend on matter at all, and we had fun, but the idea was to shake up conventional thinking of biologists where they only would recognize as life something that could be cultured by them and then published. Albert Sangiorgi once said that a drug is something that, injected into an animal, produces a paper. A microorganism is something which when put in one of its favorite culture media leads to a paper. Nowadays you might say it leads to a DNA sequence, which would be a different argument.

VENTER: But eventually a paper.

SHAPIRO: Eventually a paper. The term exobiology was coined by Joshua Lederberg in the early 1960s to describe any life forms found outside of Earth. In the 1990s it got resurrected at astro-biology, which defined itself as the science that encompasses all life, past, present, and future. Which swallows all of biology and then burps — and if anything exo is ever found, it will swallow that too. So it can't be accused, as exobiology once was, of being the only subject that had no subject matter to study.

In any event, I helped him write that book, and tried to use my imagination as best I could to envisage other life forms, different than Earth.

For example, water, thought so precious as a solvent, is hardly indispensable. In fact, for organic chemists, almost all of the famous reactions in most of the chemistry they do are run in solvents in which water is rigorously excluded in and the first step you take in doing the work up is to shake your product solvent, which might be chloroform or something like that, with water, and then you throw away the water because it has the uninteresting stuff. So that most known organic chemistry is the chemistry of gasoline, so to speak. And water chemistry is the exception. That being the case, it was not hard to envisage life functioning in organic solvents.

Of course at that point there was no thought that there might be any organic solvent anywhere in the universe. Now we know otherwise — there are lakes of liquid methane on Titan. Pretty chilly, but part of our thinking was to free ourselves from what you might call the tyranny of the covalent bond — thinking that covalent bonds were the only thing of which life could be constructed. And at low temperatures, much weaker bonds that play a minor role in Earth biology, unless they're multiplied by the thousands, as they are in DNA, could fulfill the function of covalent bonds, whether a hydrogen bond broke, or made, might be momentous event.

Or at other higher temperatures, most carbon compounds are incinerated or fly apart and the bonds break, but silicates are perfectly stable so I can see magna life — life in molten silicon — living inside of the Earth.

Now some of these things would be difficult to test for, but the idea to get across is that there's nothing sacred about the idea of water — that a fluid would do anything that could promote reactions or interactions. And then we went to carbon and decided that yes, carbon was very convenient. As Gary used to say, all of my best friends are made of carbon. But we couldn't see why it was indispensable, in the realm where there's a hundred plus elements, some of which could bond with others, silicon-silicon bonds are weaker than carbon, but they might function at weaker temperatures. Silicon-to-oxygen-to-silicon bonds are much stronger than carbon-carbon bonds and they could function at higher temperatures.

At this point the Viking experiments hadn't been run, and having explored Mars and come out with ambiguous results, well, I went to American Association for Advancement of Science meeting and a congressman was the key speaker, and he said, you gave us a billion dollars for the Viking mission to tell us whether or not there was life on Mars, and we have demanded the answer, and 'no' is an acceptable answer, but the one thing we won't tolerate is a request for another billion. Thank you.

NASA promptly moved into the No, there is no life on Mars position. There's something called the Munch Report, which talked about all the interesting geology that could be done on Mars without paying any attention to life, and there was a whole decade in which nothing flew to Mars, because to investigate the geology of Mars, wind erosion, water without reference to life, well, there was no public interest and no congressional funding.

In the interim, looking for topics to get amused with, I got into the question of the origin of life, and knowing the DNA chemistry that I did know — and helped write — I looked at the papers published on the origin of life and decided that it was absurd that the thought of nature of its own volition putting together a DNA or an RNA molecule was unbelievable.

I'm always running out of metaphors to try and explain what the difficulty is. But suppose you took Scrabble sets, or any word game sets, blocks with letters, containing every language on Earth, and you heap them together and you then took a scoop and you scooped into that heap, and you flung it out on the lawn there, and the letters fell into a line which contained the words "To be or not to be, that is the question," that is roughly the odds of an RNA molecule, given no feedback — and there would be no feedback, because it wouldn't be functional until it attained a certain length and could copy itself — appearing on the Earth.

Christian de Duve, the Nobel laureate, once wrote a letter to Nature which was headed, 'Did God Make RNA?' Because it's hard to think of any other manner in which RNA out of purely abiotic chemistry would assemble itself on the early Earth. Seeing this area called prebiotic chemistry, I decided, my major attention still being funded by National Cancer Institute, and devoted to how chemicals can rip apart DNA as a hobby essentially, I started publishing papers which disassembled — deconstructed, if our German friend wants — so-called prebiotic chemistry, and showed that in every case the result was due to the flagrant interference of the investigator in biasing the results to attain the results that he wanted.

At one point I went and spoke to the now, unfortunately, late Stanley Miller, and asked him about the circumstances of his famous Miller-Urey experiment — the one with the electric lightning and amino acids were formed — and he handed me a biographical piece he himself had written to something called the Transactions of the Copernican Society or something like that, and he described how in building his apparatus he was concerned with questions of safety, because if you take a flask and you mix it with methane and hydrogen and ammonia, the most likely result is BOOM, with flying glass in all directions, which is definitely not publishable.

With regard to safety, he built a certain apparatus, let it run for a number of days, and at the end of the days he looked at what he'd found and he found the class of chemicals called hydrocarbon — the stuff that makes up the lakes on Titan but no amino acids whatsoever. And he looked at this and he said, this isn't interesting. And he threw it out. He redesigned the equipment: he said, I was over-cautious. This is not likely to explode. He interchanged the spark and the condenser and he re-ran the experiment, and this time he got amino acids and not hydrocarbons, and he said, Ah ha! And he published.

Thus we have the famous Miller-Urey experiment showing the inevitability of amino acids on the primitive Earth. And of course the apparatus itself has no resemblance whatsoever to the primitive Earth. One of the popular magazines said that if his apparatus had been left on for a million years, something like the first living creature might have crawled out of it. And I say, if he'd left his apparatus on for a million years, he would have run up one hell of an electric bill. But nothing further would have happened because the spark was in the atmosphere and he'd used up all of the chemicals with carbon in the atmosphere, and the amino acids, which aren't volatile — they don't fly, so to speak — were safely ensconced in the water solution, and the water solution was a collection of non-volatile compounds, well, and the volatile compounds ended up in — so when an experiment goes wrong in organic chemistry you get a black gook and you reach for the potassium bichromate and sulfuric acid — mixed together it's a called cleaning solution — that cleans out about 90 percent of the failed organic experiments that are ever run.

You use that and you can get rid of the tars in about 80 to 90 percent of his carbon, this stuff that had unfortunately flown again and again until it got zapped and ended up as tars on the wall of his flask. Well, this was the best prebiotic experiment ever run, because at least he started with components that hypothetically could have been on the early Earth.

Since then, so-called prebiotic chemistry, which is of course falsely named, because we have no reason to believe that what they're doing would ever lead to life — I just call it 'investigator influenced abiotic organic chemistry' — has fallen into the same trap. In the proceedings of the National Academy of Sciences about two months ago there was a paper — I think it was theoretical — they showed that in certain hydro-thermal events, convection forces and other attractive forces, about which I am unable to comment, would serve to concentrate organic molecules, so that organic molecules would get much more concentrated in the bottom of this than they would in the ordinary ocean.

Very nice, perhaps it's a good place for the origin of life, and interesting finding, but then there was another commentary paper in the Proceedings by another invited commentator, who said, Great advance for RNA world because if you put nucleotides in, they'll be concentrated enough to form RNA; and if you put RNA in, the RNA will come together and form aggregates, giving you much more chance of forming a ribosome or whatever. I looked at the paper and thought, How did nucleotides come in? How did RNA come in? How did anything come in?

The point is, you would take whatever mess prebiotic chemistry gives you and you would concentrate that mess so it's relevant to RNA or the origin of life — it's all in the eye of the beholder. And almost all of prebiotic chemistry is like this; they take chemicals of their own selection.

People were talking about Steve Benner and his borate paper where he selected, of his own free will, the chemical formaldehyde, the chemical acid-aldehyde, and the mineral borate, and he decided to mix them together and got a product that he himself said was significant in leading to the origin of RNA world, and I, looking at the same thing, see only the hands of Steve Benner reaching to the shelf of organic chemicals, picking formaldehyde, and from another shelf, picking acid-aldehyde, etc. Excluding them carefully. Picking a mineral which occurs only in selective places on the Earth and putting it in in heavy doses. And at the end getting a complex of ribose and borate, which by itself would be of no use for making RNA, because the borate loves to hold onto the ribose, and as long as it holds onto the ribose it can't be used to make RNA. If it lets go of the ribose, then the ribose becomes vulnerable to destruction by all the other environmental agents.

The half-life of pure ribose in solution, a different experiment and a very good one, by Stanley Miller is of the order of one or two hours, and all of the other sugars prominent in Earth biology have similar instability.

I was publishing papers like this and I got the reputation, or the nickname in the laboratory of the prebiotic chemist, of 'Dr. No'. If someone wanted a paper murdered, send it to me as a referee. And so on. At some point, someone said, Shapiro, you've got to be positive somewhere. So how did life start?  And do we have any examples of authentic abiotic chemistry, not subject to investigator interference?

The only true samples we have are those meteorites, which are scooped up quickly and often fallen in an unspoiled place — there was a famous meteorite that fell in France in a sheep field in the 1840s and led to dreadful chemistry of people seeing all sorts of bio molecules in it, not surprisingly. But if you took pristine meteorites and look inside, what you see are a predominance of simple organic compounds. The smaller the organic compound, the more likely it is to be present. The larger it is, the less likely it is to be present. Amino acids, yes, but the simplest ones. Over a hundred of them. All the simplest ones, some of which, coincidentally, overlap the unique set of 20 that coincide with Earth life, but not containing the larger amino acids that overlap with Earth life. And no sample of a nucleotide, the building block of RNA or DNA, has ever been discovered in a natural source apart from Earth life. Or even take off the phosphate, one of the three parts, and no nucleoside has ever been put together. Nature has no inclination whatsoever to build nucleosides or nucleotides that we can detect, and the pharmaceutical industry has discovered this.

Life had to start with the mess — a miscellaneous mixture of organic chemistry to begin with. How do you organize this? You have to have a preponderance of some chemicals or lacking others would be against the second law of thermo-dynamics — it violates a concept that as a non-physicist that I barely grasp called 'entropy'.

How does one get around this? Entropy is like a business. It doesn't matter if one subsidiary of the business loses money as long as the others show enough profit to offset it. What you need is a larger system, the environment, and part of it absorbs energy and gets organized, and in payment for that, the rest of the environment gets disorganized, usually by going up a little bit in temperature, which is the common denominator of entropy. If you convert other kinds of energy to heat, you can pay for a lot of organization.

With just these concepts and with a lot of papers scattered in the literature that hadn't been pulled together, including some excellent ones by Harold Morowitz, a physicist who can be very eloquent on the subject. You get the idea that life could start in mixtures of simple molecules, provided that the organization of these molecules was intimately connected to the release of some energy as heat if there was coupling.

In the simplest case, and there may be many more elaborate cases, they found that the energy wouldn't be released unless some chemical transformations took place. If the chemical transformations took place then the energy was released, a lot of it is heat. If this just went on continuously, all you do is use up the energy. Release all of it and you've converted one chemical to another. Big deal. To get things interesting, you have to close the cycle where the chemicals can be recycled by processes of their own, and then go through it again, releasing more energy. And once you have that, you can then develop nodes — because organic chemistry is very robust, there are reaction pathways leading everywhere, which is why it's such a mess.

Well the fact that this cycle, this energy-driven cycle, was working would suck the material out of all these other side-reactions into the main cycle. Occasionally some step, due to change in environment, and the main cycle would be blocked: the acidity would change, the temperature would change, and then the machine would cease to turn. But in wandering around the many pathways, a bypass might be found and the cycle would reestablish itself again. And in searching for that bypass some catalyst might be found that would unblock the main cycle.

The main idea is that you get a network of reactions, which would feed into each other, and the net result would be that the latent energy would be released. One of the most familiar kinds of chemical energy for the chemist is redox energy; you get an electron-poor reagent (an oxiding agent technically), an electron-rich reagent (a reducing agent technically), and the electron-rich reagent gives electrons to the electron-poor reagent.

In planets from the Earth are subject to a sort of tension because the inside, which is pure iron, is very electron-rich, while the outside, due to continual escape of hydrogen into space because water gets broken up by radiation, is electron-poor, so that at various places on the Earth there will be interfaces where electron-rich molecules are interfaced with electron-poor molecules. These are then prominent sites for the origin of life. Everyone can have his own favorite site. Some argue for the interiors of volcanoes, some argue for vents, some argue for the monolayer of the space of the ocean.

The idea is that this is inherent in the laws of chemistry and physics. One doesn't need a freak set of perhaps a hundred consecutive reactions that will be needed to make an RNA, and life becomes a probable thing that can be generated through the action of the laws of chemistry and physics, provided certain conditions are met. You must have the energy. It's good to have some container or compartment, because if your products just diffuse away from each other and get lost and cease to react with one another you'll eventually extinguish the cycle. You need a compartment, you need a source of energy, you need to couple the energy to the chemistry involved, and you need a sufficiently rich chemistry to allow for this network of pathways to establish itself. Having been given this, you can then start to get evolution.

This segment is part of the environment, which you can call an organism, a cell, a life-container, starts to change to adapt, become more efficient at harnessing the energy. If, as Freeman Dyson said, you want to diversify, well, if it were a spherical object, something might shatter it into two pieces. Each piece would contain half of the necessary set of molecules; it would have two daughters. This is all analog. Digital information storage is nowhere in it.

One way of finding out, to make this clear, who is at this table today would be to hand around a piece of paper and have everyone write on a list their names, at the end of which you'd have a list which has the attendants at this table. That's DNA. However much more simply, one knows who's at this table if you're familiar enough with the people by looking around the table. And I can see that Freeman Dyson, for example, is present, but another origin-of-life chemist name Jack Sostack is definitely not present. Craig Venter is present, but many DNA sequences are not. Fred Sanger, who is the person who started that ball rolling, is definitely not present; he retired when he was 65. But this is information, too. Information just stored by the presence of the people at the table, and this was called by Doron Lancet, an Israeli theoretician, the compositional genome.

And the other part of life that involves giant molecules are the enzymes, which are wonderful catalysts, but at the start of life you may have been able to get by without wonderful catalysts — you don't need to speed things up a million-fold, which is what enzymes can do. Small molecules can in instances speed things up a thousand-fold, and if you have the right system a thousand-fold may be enough. The picture that emerges is that in a planet like Earth there may have been dozens or hundreds of separate starts of Earth — we are all the children of the most successful one, which as far as we know, dominates on the Earth. We need not be the only life form present on the Earth.

Paul Davies and others have started research, much cheaper than the space program, to try to detect life that has no DNA, and once I talked to a person who also knew something about life and bacteria, namely Joshua Lederberg, and he said an experiment he'd always wanted to run was to have a culture medium that only contained radio-active phosphate. No ordinary phosphate. Now this wouldn't bother small molecules, but if you ever tried to build an RNA or a DNA, the radio-activity emitted would inevitably shatter it into pieces. Anything that could grow in that medium would automatically not be using DNA or RNA as its central function.

It may be that novel life forms are floating by us on this table. One way of doing it would be to set up a truly extraordinary culture medium, which excluded phosphate or some other ingredient thought essential for all of Earth life, which is really better described as life as we know it, and see if life as we don't know it just happens — be sending a spore that was floating back and fell in by accident and flourished.

The same concepts apply to the search for extra-terrestrial life. If you're only looking for Earth-like planets, if you're only looking for liquid water, if you're only limiting yourself to carbon compounds, you may be missing the organisms that exist. And when people want to send DNA sequences to Mars, or anti-bodies to Mars, I say, tell me another one. The two things eventually come together. If you believe that you need to generate an RNA molecule to get to start life, then the odds are so staggering that the odds are really that Earth is the only place is the universe, allowing perhaps that it spread by panspermia that has life.

On the other hand, if you believe that life could start with good molecules, given enough energy, then the universe may be rich with start-ups, and then there may be some series of levels that you have to go through, higher and higher, in order to get life more and more advanced. And we may be one of the relatively small number of places where you have intelligent life. I don't know, we haven't detected other intelligent life yet.

VENTER: Other places may not view us as intelligent life.

SHAPIRO: They have decided that one of the eight dimensions of string theory — one of the alternative universes that are now postulated by the anthropic people, are much more habitable than this. Life has a difficult job getting started. I admit this is one extreme view of life, but it's one that makes life, as Stuart Kauffman put it, something that the universe has in a sense expected, and what one does with that fact, I leave to you.

I'm not a theologian, I'm an agnostic, which says that I really do not know what's going on. But that at least in the origin of life we have a problem that can be solved not too difficultly in a laboratory, by getting the right set of molecules, by getting an appropriate source of energy — okay, we cheat a little bit, we use a beaker as the container rather than some membrane, which is perhaps more difficult to achieve than is commonly understood, and we just try to see what happens.

Does it all turn into tar, or are molecules always cut off from the energy as in the Miller experiment, or do you get ever-increasing and intricate cycles of reactions with some of the original compounds vanishing and others increasing in great numbers. If you are, then you may have caught a picture of the start of this universal phenomenon and you have to then find bigger and bigger vats or divide it up. Don't interfere, don't look for the results you expect, just let nature teach you, see what nature wants to do, given the bait of releasing this energy, which is what nature does seem to want to do.

I've spoken at length and enough so that I have enough voice to answer any question or accept any insults from the DNA-philes that are present at the table.

LLOYD: Richard Dawkins wrote a special email for you.

SHAPIRO: Richard Dawkins wrote a wonderful book, but the place where he absolutely blew it was in a section on the origin of life. He took all of the supposed irreducible complexity and said that natural selection can explain all this, you need no other rule. But then when it gets to how does one get to natural selection, he has no other recourse — he's not a chemist — than to invoke some improbable event; he says that we need a vast improbable event and he goes anthropic and says, well maybe there are many universes and we happen to be the lucky one.

But the same type of reasoning that Richard Dawkins uses to explain evolution could apply equally well to what could be called thermo-dynamic evolution. In fact natural selection may just be one special case of thermo-dynamic evolution; there may be other forms of evolution undetected by us. So his schoolboy howler is the section on the origin of life. He writes brilliantly elsewhere. If you want to write that to him, Freeman — He hasn't written an email to me; I keep my hands off evolution, I don't claim to know very much about it.

VENTER: Maybe I come at this as a basic experimentalist — the theory behind theory is that you come up with truly testable ideas. Otherwise it's no different than faith. It might as well be a religion if there's no evidence for it. So how do you get it past your religion phase?

SHAPIRO: Instead of looking for elaborate new ways to make ribose or to connect nucleotides, if an equal amount of money were invested into telling people to just look at coupled reactions where energy is discharged in matter.

VENTER: If we're looking for life here other than DNA-based life, what should we be looking for that we're not?

SHAPIRO: Well, now we're talking about two different questions. One is how you start with inanimate life, chaotic mixtures of chemicals and under the influence you organize them, which is an event that took place here three and a half billion years ago. How you look for a shadow biosphere, life that is very different than ours, well there are very many schemes and all of them are worth trying. Graham Cairns-Smith has numerous schemes for detecting life made entirely of minerals.

I said How would one detect advanced mineral life and he said, well there are always fresh starts. And he would invest money in looking for unusual minerals — following the activity of minerals that are out of place, or growing unusually in different areas, or having interesting interactions with organic compounds, unusual catalytic effects. I would have told him my idea would just be to set up a culture medium consisting of rich minerals — someone was talking jokingly about the ultimate diet where you're not a meat-eater, you're not a vegetarian, you're not even a vegan because even vegetables are alive, you're a mineral. You eat only minerals and breathe only carbon dioxides, and that's the ultimate in dietary purity.

LLOYD: Now you've destroyed this. If now there are mineral societies, you can't even eat just minerals any more.

SHAPIRO: I may leave us all to starve, but I would just take the roof of one of those buildings in Glasgow, which looks as industrial and polluted as any place on the planet, though maybe China would be better these days, and you put in a rich mineral bath and you have a filter that excluded anything somehow, any virus or living bacterium, and you just see if anything grew. Nothing more expensive than that, you know?

VENTER: What's missing is your definition of life. It seems to encompass a broader range than maybe my definition would.

SHAPIRO: There was a wonderful paper written by Chris Chyba and Carol Cleland about three years ago about definitions of life, and how even defining what definition is can get you into philosophical doo-doo. And it's best to look for phenomena that by their properties we would be happy to classify as alive, and to not worry too much about definition.

Of course we'd want something that didn't extinguish immediately. That wouldn't be a good kind of life. One could consider a Zhabotinsky reaction as alive, or a thunderstorm, or a hail storm — but they don't evolve, they dissipate, so that isn't interesting life. What we're really interested in is interesting life — something which becomes more and more complex and adapts so it resists being extinguished.

VENTER: Does it need to be self-replicating?

SHAPIRO: It needs to be reproduced. The idea of a replicator, of DNA copying itself. I have a tie like that: it shows nucleotides swimming up to DNA, and miraculously one strand forms a double helix, but anyone who teaches biochemistry knows that doesn't happen — no way. There are dozens of proteins that come in and get involved in the action, and untwist the twists of DNA, and prime it and close the gaps in DNA.

VENTER: I wasn't describing a mechanism, just, the term 'self-replicating'.

SHAPIRO: DNA isn't self-replicating.

VENTER: No, I'm not talking about DNA.

SHAPIRO: And RNA as far as I know isn't — virus needs an entire cell filled with ribosomes and god knows what — mitochondria.

VENTER: Methanococcus is self-replicating.

SHAPIRO: Methanococcus is self-replicating, and if it lives and grows and changes eventually into different strains, that's alive.

LLOYD: So is a virus alive?

SHAPIRO: That's a question of how you want to define it.

VENTER: Is it not self-replicating.

LLOYD: I'm not self-replicating either. I have children and neither of them look anything like me.

SHAPIRO: The difficulties in these definitions are notorious. Is a nun alive? She's certainly not replicating. Is a mule alive? It has most of other properties, but it's sterile and has no offspring.

CHURCH: Its cells are alive.

SHAPIRO: Its cells are alive.

VENTER: If we're looking for life, it helps to know what we're looking for in some form.

SHAPIRO: Yes, I would design missions to Mars to follow the carbon, not the water. They've detected methane now in the atmosphere, and I would have orbiters that sniff that methane and looked for the place where it was coming out of the ground and then analyze whatever organic chemicals might be emitted there. Out of the nature and identity of those organic chemicals, I would come to a conclusion about whether something of interest is present there or not, and decide if missions should be flown to investigate that site in greater depth.

VENTER: My other question is, I don't understand your dismissal of Stanley Miller's experiments.

SHAPIRO: I'm not dismissing — he was really addressing a very separate and valid scientific question, which is how did Earth come into its carbon reservoir. I mean we know there is carbon in various forms on the Earth.

VENTER: But isn't the spontaneous formation of the amino acids that he showed still valid? And if not, why not?

SHAPIRO: Well, if Earth had an atmosphere of methane, predominantly methane, which is a highly debatable subject, which the geologists are arguing about...

VENTER: There's a question how applicable it is to the Earth, but the question is, with that mixture did he not really get spontaneous formation of amino acids.

SHAPIRO: He got spontaneous formation of the two simplest amino acids in reasonable amount, plus very trace amounts of other amino acids, and some amino acids that are not present and made no use of in biology, and the organic compound he got in greatest amount in something called formic acid, which is secreted by some ants as part of their venom but plays no other role as such in Earth biology.

VENTER: So you're saying his experiments are valid, they're just not applicable.

SHAPIRO: They don't tell us anything about the origin of life, they tell us one way in which more complex carbon compounds, more complex than methane, were formed. Other alternatives are that they were brought in by heavy in fall of meteorites or comets, or else that they got trapped in the center of the Earth and were out gassed by volcanoes, and volcanoes to this day are out gassing carbon monoxide and methane phyol, that by itself could not start life alone. There's another possible source of the carbon. His was an authentic contribution to that question, it was not a contribution to the origin of life per se. It didn't answer what happened next, which is the crucial question.

LLOYD: It sounds consistent with the finding of simple amino acids in meteorites. He did a simple experiment in which he produced simple amino acids, and then we see these simple amino acids in meteorites, so it almost sounds like it's okay to assume that simple amino acids would be available as part of the chemical soup from which you could concoct life.

SHAPIRO: I would say it's okay to assume that simple amino acids were present in the early oceans, but at great dilution such that ten to the minus fifth molar is the best estimate that I've seen — or lower. And at that dilution very little of interest was likely to have happened. Places where for some reason carbon compounds were concentrated, due to whatever effect and by whatever mechanism, are perhaps more likely environments as the place where life began. And there may have been more than one solution, there may have been many starts of life, and we're simply sitting here as the children of the most successful one.

PRESS: Are you suggesting we should be doing a million Miller-Urey experiments, do combinatorial exobiology, look at many many different types of conditions and see where you get the kinds of simple molecules that you're talking about?

SHAPIRO: No, we can draw clues from existing life as to the type of molecules one should be looking at. Catalysis by minerals, which is catching on, was an important part, and certainly oxidation and reduction by minerals was another important part, so I would look at interfaces between minerals and aqueous media as a very promising place to look. One might look at places where primitive organic compounds or even carbon monoxide itself was emitted from the Earth as one possibility, and deep-sea vents offer this reason very popular places. 

Günter Wächtershäuser, who's only occasionally leaking what he's doing, is working on minerals and for a time he very heavily favored iron pyrites as a very likely mineral because it's oxidization and reducible, and because certain of our key enzymes contain clusters of iron and sulphur, which he regards as authentic relics of the oldest life.

If you think that phosphate was important from the very beginning, then those places on Earth which are very rich in phosphate, or better yet in pyrophosphate, minerals of pyrophosphate, if any existed, might be very likely places — those exposed to water. Again, if those minerals had any tendency to collect organic compounds in their interstices, that would be another site worth investigating. All of these sites are worth investigating. 

In some places you might start a form of life that doesn't lead in the direction of the life we know. So much the better. The events that started out type of life may have been in an environment, which no longer exists on the face of this planet. And environments that we might investigate today, or ones we might concoct in a test tube, might lead to different kinds of life again.

But the study reactions where energy, say, present in minerals are discharged and there's a steady flow of simple organics in some sort of flow reactor, and one just sampled what the content of organic chemicals formed in such reactions was, without any prejudice, would be very interesting. One could take hints, if Wächtershäuser likes, pyrites: very good, that could be the mineral of choice. If Steve Benner thinks that life started in borates, well, wonderful. Let him pour streams of simple formaldehyde through borates from now until doomsday, and if cycles begin I will bow my head in his direction.

VENTER: But maybe we're looking for an answer that didn't even exist, maybe it didn't originate of Earth at all. Given the statistical probability of some of the events you're talking about, panspermia has a wonderfully high probability if life exists almost everywhere else in the universe.

LLOYD: But it had to start somewhere.

VENTER: Yes, but we could be looking at totally the wrong environments.

SHAPIRO: But there are so many different environments, so much energy of all sorts being shot out of volcanoes, given off by lightning, pouring down in all sort of radiation — this is a very likely place, much better than, say, the moon.

SASSELOV: That's certainly a possibility, but we'll have an opportunity to actually experimentally look for that because there is not that much time in this young universe to spread the seeds so to say. So these environments must be very common.

VENTER: Yes, and they should be common.

SHAPIRO: I'm very in favor of environments that look for life on Mars. I wouldn't start by looking for silicon life, because we don't know anything about silicon life, and we do know something about carbon life — so if there was carbon life but it was different than our own I think we have a fair chance of identifying it somehow.

VENTER: If there is silicon life, do they live in glass houses?

SHAPIRO: They may excrete glass houses — that could be their waste product.

LLOYD: Which brings me to a question about this hypothetical non-carbon-based life that might be here on Earth. When you have one of these systems, it has a metabolism — so it's taking in energy, and different chemicals, and excreting energy in other forms of a higher entropy content but presumably not at maximum entropy, the stuff that they're excreting. When that happens, you have a source of free energy and one thing that life is very good at is finding sources of free energy and then taking advantage of it. It seems strange to talk about another thing out there metabolizing that's different from ordinary life, and yet that's hard for us to detect. Surely something like that would actually be being taken advantage of by regular life — wouldn't we be able to see its signature there?

SHAPIRO: Perhaps, if regular life existed in that environment. That environment might be inimical to regular life. For example because it was utterly depleted in phosphate, to name one thing, or because the temperature was much too cold for regular life to exist, but life that worked on much weaker chemical bonds might flourish there.

LLOYD: What I'm suggesting, if the stuff is there and it's in an area where there are other living things around, then other living things are presumably eating this, or eating the byproducts of this.

VENTER: Something like methanococcus does live on just minerals and inorganics — it's a true autotroph. Autotrophs exist quite abundantly in nature. CO2, hydrogen — it doesn't take any organics presumably, or doesn't need to, for life. So you could say that that's evidence for mineral forms of life.

PRESS: I just want to clarify the definition that you're working with here — you're talking about looking for life in terms of a metabolism and energetics — you're not really dealing with the whole question of self-replication, is that right?

SHAPIRO: 'Replication' is a word that's gotten too tied to the idea of DNA, digital information storage. I'm talking about the topic that Freeman referred to earlier, which has the broader name of 'reproduction'. Somehow the entity, call it what you will, becomes two entities, or three, each of which has the functionality and the capabilities of the original entity.

DYSON: I'd like to raise another question, which is the question of a vacuum life — most of the universe if a good vacuum, most of the habitat, probably 99.9 percent of the real estate, is small objects — asteroids and comets, dust, grains, all kinds of things. We are the exceptions; we happen to live in an atmosphere. We have been biased to think that you should look on other planets.

But in point of fact I consider it vastly more likely if there is any external life that it's not on planets at all. And of course once life is in a vacuum it has the enormous advantage — it's much easier then for it to spread from one place to another. Life that's adapted to an atmosphere first of all has a very hard time to get away from a planet, and secondly it's very unlikely to hit another planet with an atmosphere. So the probability that it will spread is very small.

SASSELOV: Freeman, do you suggest that this is a possible pathway to life? Or only life that's adapted to live in vacuum?

DYSON: I say both. It could be. I'm assuming it originated in a vacuum, because that's where most of the habitats are.

LLOYD: Yes: you need a source of free energy, and you need flows of materials. Well the surface of a comet has sources of free energy, and just in the same way that you were saying a good place to look for prebiotic life, as it were, on Earth, would be at a mineral-aqueous interface, the interface between the surface of a comet of a vacuum has the same features that you might require from this mineral-aqueous interface.

DYSON: Right — not that we shouldn't look for planets, but that it's stupid to concentrate one's attention on planets to the extent that we are.

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