Stanley Miller Downloaded from by Guest on 30 September 2021 Neil A

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. . Stanley Miller Downloaded from http://online.ucpress.edu/abt/article-pdf/51/6/349/44208/4448946.pdf by guest on 30 September 2021 Neil A. Campbell

As a chemical system, what most distinguishes life Biology and chemistry are allied sciences. Nowhere is their in- terdependencemore evident than in the study of the origin of life. from nonliving matter? Chemists and biologists have long speculatedabout the conditions "The essential difference between life and nonlife is of primitiveEarth and how that environmentcould have given rise replication. There are other differences, but this is to the precursorsof living cells. the essential one. In addition to replicationthere has In 1953, when Stanley Miller was only 23 years old, he per- formed an experimentthat would attractglobal attention. In a lab- to be mutation, with the mutations transmittedto the oratoryat the University of Chicago, Millerattempted to simulate progeny. Thus the origin of life is the origin of repli- the chemicaldynamics of the primordialEarth in a glass apparatus cation with mutation. Another way to state this is that he constructed. His landmarkexperiment was the first to test the hypothesis that, given the right conditions, the buildingblocks that the origin of life is the origin of evolution, since of life could originate from simple chemicals. In this interview, reproduction or replication, mutation and selection Millershares the events that led to his experimentand the results result in Darwinian evolution." that brought the world a step closer to understandinghow life on Earthbegan. You're best known for your experiments demon- Today Miller is professor of chemistryat the Universityof Cali- fornia at San Diego where he continues his researchon the pre- strating that organic molecules could have been pro- biotic synthesis of organiccompounds. In addition to his research, duced on the early Earthbefore there was life. What Miller teaches courses in biochemical evolution, molecular bio- is an organic molecule? chemistryand physical chemistry. "The old definition, 150 years ago, was a molecule that came from living organisms. It was felt that carbon compounds, except carbon dioxide and Thinking back to your student days, can you recall carbon monoxide, came only from living organisms how you chose your schools-Berkeley for your un- and had some sort of vital force in them. But we now dergraduate education and the University of Chi- know that there is no vital force, and organic com- cago for graduate school? pounds are just those that contain carbon." "I chose Berkeley because it was logical-right near my home in Oakland, and it was a good school. It's also to from home. As for Thisinterview is oneof eightwhich will appearin The American costly go away graduate Biology Teacher in its September1989 throughJune 1990 school, the Chemistry Department at Berkeley did issues.All areexcerpted from conversations between eminent biol- not allow undergraduatesto continue on as graduate ogists and Neil A. Campbell,author of the textbookBiology students. This is common in chemistry departments. (Benjamin/CummingsPublishing Co., RedwoodCity, CA). The feeling is that chemistry is so diverse that stu- Theinterviews introduce each unit of the secondedition of Bi- dents should broaden their ology, to be publishedin January.This interviewwith Stanley perspective by attending Millerwill befollowed by similardiscussions with JaneGoodall, a different school. I talked to a number of professors Bill Schopf,Nancy Wexler, George Bartholomew, Niles Eldredge, about which was the best place to go and, at the CharlesLeblond and RuthSatter. time, Chicago seemed the best choice. The real Campbellhas taughtgeneral biology to a varietyof studentsat problem was whether or not the stipend that I was CornellUniversity, Pomona College and San BernardinoValley offered was adequate. Although shopping around Collegefor thepast 21 years.Now at the Universityof California, Riverside,Campbell has invested11 yearsin the developmentof for the biggest fellowship is not a good thing to do, Biology. you have to have enough money to live on."

MILLER 349 What experiments were historically important in compounds. He tried to talk me out of it and get me dispelling the myth that organic molecules are to do another project. When he realized I was deter- products of special vital forces? mined, he explained that he felt this experiment was "The example that is usually cited is Wohler's syn- very risky and he was responsible for making certain thesis of urea in 1828, in which he took ammonium that I could come up with a Ph.D. thesis in two or cyanate and converted it to urea, which is a product three years. So we agreed that we would try it for six of animal metabolism. But the idea didn't catch on months or a year, and if nothing came out of it, we until people started making acetic acid and other or- would go back to something conventional. But since ganic compounds from starting materialsnot derived we obtained encouraging results quickly, there was from living organisms." never any question that we would continue with it." Prior to your experiments in the early 1950s, what When Urey described your proposed experiment at a was the prevalent view among biologists about the seminar, a doubtful listener asked, "And what do origin of the first organic molecules? you expect to get?" Urey replied "Beilstein." What "As far as I can tell, they really didn't think much did he mean? about it. There was just no rational explanation. "He was referring to Beilstein'sHandbuch der Organi- What was usually proposed was that life arose by an schen Chemie.It used to be a single volume, but by extremely improbable event. There was Oparin's now it has grown to about 400 volumes. These Downloaded from http://online.ucpress.edu/abt/article-pdf/51/6/349/44208/4448946.pdf by guest on 30 September 2021 theory that had been around since 1938 which pro- volumes contain a list of properties of every organic posed that there was an abundant organic soup, and compound that has been reported, a few million by that the first organisms were derived from these pre- this time. And what he meant was that we would get biotic organic compounds and ate them rather than every possible type of organic compound formed making their own." more or less randomly." If organisms didn't make the organic substances When you actually cranked up your apparatus to present in this primordial soup, then what was the simulate early Earth conditions, what did you source of these molecules? make? "Oparin proposed that the primitive atmosphere "The surprise was that we didn't get Beilstein, we contained the gases methane, ammonia, hydrogen got mainly organic compounds of biological signifi- and water, and chemical reactions in that primitive cance. And the amino acids were formed, not in trace atmosphere produced the first organic molecules. quantities, but abundantly! The experiment went That hypothesis had a good deal of appeal, but beyond our wildest hopes." without experiments, it was talked about but not What are amino acids? very well accepted." "Amino acids are the building blocks of proteins. What did you propose to do as an experiment to test There are 20 of them that occur in proteins, but there the hypothesis? are many thousands more that are possible. Since "Harold Urey, my advisor at the University of Chi- proteins are important to living organisms, making cago, knew that it was more reasonable to make or- amino acids would be considered very important." ganic compounds from the reduced gases in the pro- What was the physical appearance of the soup that posed primitive atmosphere than in our modern at- you made in your discharge apparatus? mosphere. But after some discussion, it was felt that "The first time I did the experiment, it turned red if methane, ammonia and water were combined and after sparking overnight. Very dramatic!And then just left to sit, organic compounds would not be after it turned red, it got more yellow and then made. Energy must be added. And for the source of brown as the sparking went on. The experiment is energy, the choices would be ultravioletlight or elec- easily reproducible with the exception of this red tric discharge (a spark). Ultravioletlight is difficultto color." work with, so we settled on an electric discharge, which was handy around most chemical labs in the After you'd been on your project for about three and form of a vacuum leak detector. The plan was to sim- a half months, you were ready to publish your first ulate the primitive atmosphere in a glass apparatus, paper reporting your results. Graduate students energize the mixture of gases with an electricalspark usually list their advisors as coauthors on their and see if I made any organic molecules." manuscripts, but when you took your paper to Urey, he suggested that you remove his name from the When you first proposed the experiment, what was manuscript. Why was that? Urey's initial reaction? "Well, he felt that if his name had been on the paper "Well, I went up to Urey and told him that I wanted he would have gotten all the credit and I would have to do this experiment testing his ideas about the gotten none. So he took his name off. And even at primitive atmosphere and the synthesis of organic that, it's known as the Miller-Ureyexperiment. And

350 THE AMERICAN BIOLOGY TEACHER, VOLUME 51, NO. 6, SEPTEMBER 1989 it's probably the thing he's best known for, with the team at the NASA Ames Research Center, it turned exception of the discovery of deuterium-for which out that amino acids were present at the parts per he won the Nobel Prize-and his work on the atomic million level. These amino acids were very similarto bomb." the ones that had been made in the electricdischarge 15 years earlier. They did, however, find some addi- After the first paper was published in Science, Urey tional amino acids that I had not obtained. So I re- expressed concern that the amino acids formed in peated the electric discharge experimentswith a little your discharge apparatus could have been made by modification, and I was able to show that all the bacteria contaminating the glassware or solutions. amino acids found in the Murchison meteorite were How did you respond to this concern? also obtained in the electric discharge apparatus. "Someone at a seminar had needled him that there The significance of this is that we had been doing were probably bacteria in there contaminating the these prebiotic experiments not knowing whether solutions. He came back quite concerned and told me this really took place on the primitive Earth, or if it that if I had made a mistake, it would be better for was just a model experiment that bore no relation to me to retract than to be proven wrong by someone reality. The similarityof the Murchison organic com- else. I knew that there were bacteriaaround since the pounds and the electric discharge compounds shows solutions were not handled under sterile conditions, that this kind of synthesis took place on the parent Downloaded from http://online.ucpress.edu/abt/article-pdf/51/6/349/44208/4448946.pdf by guest on 30 September 2021 but I also knew that they were not synthesizing the body of the meteorite, probably an asteroid. This compounds-you could see some of the organic ma- makes it plausible, but does not prove, that similar terial actually being formed and dripping off the syntheses took place on the primitive Earth." electrodes. I decided I was going to put an end to this doubt. I took the whole glass apparatus, filled it up A few biologists have speculated that the first or- with the gases, sealed it off, put it in an autoclave for ganic molecules on Earth arrived with extraterres- 18 hours instead of the usual 15 minutes required to trial rocks such as the Murchison meteorite. What is kill bacteria.I then sparked the mixture and obtained your reaction to this idea? the same results I had from the apparatus that had "Some organic substances certainlycame in this way. not been sterilized. No one has raised the issue of There are problems with the survival of organic com- sterility since then." pounds on meteorites larger than a few meters in di- ameter, because they are not slowed up by the atmo- Did other labs rush to repeat your experiments after sphere before colliding with the earth. In addition, you published? sugars do not occur in Murchison, so some of the "It's hard to say. One or two did, because they pub- prebiotic synthesis must have occurredon the earth. lished papers saying that they had obtained similar And I think that all but a few percent of the synthesis results. I suspect that others repeated it without re- was done on the Earth." porting it. After a while, many experiments of this type with variations were done and a substantial Why doesn't such organic synthesis occur at the body of work has been accumulated." present time with our currentatmosphere? "Organic synthesis of that sort does not take place In 1969, a meteorite fell in Murchison, Australia. now because of the presence of oxygen, although Chemical analysis of the Murchison meteorite plants of course can do it." showed that it contained organic molecules. How does this discovery relate to your experiments on the Each amino acid occurs in these two, three dimen- origin of organic molecules? sional forms-left- and right-handed versions that "What fell in Murchison, Australia (which is about mirror one another. In your prebiotic synthesis ex- 300 miles north of Melbourne) was a meteorite that periments both forms are produced, and yet only contains organic material.There previously had been the left-handed molecules are common in life, espe- a number of these organic-containingmeteorites that cially in proteins. How do you account for this? had fallen and had been sitting in museums. They "Well that's been an outstanding question for a long unquestionably contained organic material, but time. There really is no good explanation for how when they were analyzed for amino acids and other this came about. All prebiotic syntheses give equal organic compounds there were two problems. One quantities of the right (D) and left (L) forms. In fact, was that while sitting in the museums they had been you can tell whether or not you've got contamination contaminated, and the other was that the analytical if there's an excess of L-amino acids or D-sugars. methods at the time were not adequate to detect and That was the reason the amino acid analysis of the identify the small amounts of organic molecules. But Murchison meteorite was convincing-there were by 1969, when the Murchisonmeteorite fell, the ana- equal quantities of the D and L forms. Without that, lytical methods had improved and the meteorite was the presence of amino acids would have shouted fresh, so there weren't quite the contamination "contamination."There are a number of rational ex- problems. So when the meteorite was analyzed by a planations why living organisms have all L-amino

MILLER 351 acids and D-sugars-it has to do with selective ad- just do not know when life began during the pe- vantage and the ease of synthesis. Although we riod." don't know how this came about, I'm convinced that In what sort of place do you think life began on it happened about the time of the origin of life or Earth? shortly thereafter." "The usual assumption is that it began in the ocean. But why don't we have both "left-handed" and But you can legitimately propose that some of the "right-handed"species? processes occurred in different areas. For example, "This is a common question I get asked. An all D-or- some of the polymerization reactions that made ganism is as good as an all L-organism.If life arose larger organic molecules probably occurred on only once, then it was by chance that it used L-amino beaches that had dried out and heated up, and some acids, but it could, with equal probability,have used may have occurred in hot springs. But the oceans all D-amino acids. If life arose many times, there form the bulk of the area where organic reactions would have been equal numbers of D- and L-or- could take place, and I think most of the chemistry ganisms. In the course of time, one of these would took place there." have acquired a selective advantage and would have One hypothesis is that the first organisms arose in outgrown all the others."

the hot water around volcanic vents on the sea floor. Downloaded from http://online.ucpress.edu/abt/article-pdf/51/6/349/44208/4448946.pdf by guest on 30 September 2021 When you were first proposing your experiments You and a colleague, Jeffrey Bada, have challenged and doing your experiments on prebiotic organic this view in a recent publication. Would you de- synthesis, were you already thinking of this as a scribe your experiments? first stage in the origin of life? "The proposal was that life originated in submarine "Of course. We understood the implications of our vents. Water flows out of these vents at 350?C.This results; we would not have done the experiment as water is sea water that flows through the deep sea an exercise in chemical synthesis." sediments and is heated by molten rock. The water comes out in a matter of minutes through these black After your provocative paper appeared in the smoker chimneys and then cools. Living around journal Science, was there much reaction in the these vents are some very interesting organisms. press? There are tubeworms, clams and the like. These or- "Oh, yes. There was a deluge of requests for inter- ganisms are not living at 3500, but at around 37?. And views and pictures. I was really quite surprised. Time they live off the metabolic products of bacteria in a magazine had a whole page on the experiment. symbiotic relationship. There was a Gallup poll taken on whether or not The hypothesis is that water and gases start out at people felt life could ever be made in a test tube. The 3500, the amino acids are made, polymerized in the opinion was largely no." vents, and then somehow the proteins and other Assuming that mechanisms similar to those at work polymers are organized into living organisms by the in your laboratory simulations produced organic time they get out of the vent. The problem with this molecules on the early Earth,what were some of the hypothesis is that organic compounds cannot be syn- subsequent developments that were important to thesized at 3500:they would be destroyed. We did an the origin of life? experiment to illustrate this by taking some amino "The essential process is that of self-replication.Thus acids and heating them up in a sealed tube to 3500. we need to find the prebioticpolymers that can con- They decomposed before we even got them to that tain genetic information. These may be RNA-like temperature. Furthermore,you can make polymers molecules, but they could be quite different." by heating amino acids, but you have to heat them dry. Well, in a submarinevent it is obviously not dry. How early do you think life began on Earth? Even if you get polymers such as polypeptides, that "Nobody really knows. The Earthis 41/2billion years is not a living organism by any means-it has no ge- old. And the earliest evidence for life is about 31/2bil- netic material. So on three or four counts the hy- lion. So there's a billion year period in between. pothesis is invalid." There have been various proposals about the temperature of early Earth-that it was cold when it formed If prebiotic synthesis of organic compounds led to or that it was molten. But prebioticsynthesis did not the origin of life here on Earth,do you think this is a start until the Earthgot down to a low enough tem- common process elsewhere in the universe? perature for the organic materialto be stable; that is, "I feel it is. But the problem is that we don't know below about a hundred degrees. We're not sure that much about the subsequent steps. Making or- when that happened, but we can assume about 4 bil- ganic molecules such as amino acids purines, pyrimi- lion years ago. That still leaves hundreds of millions dines and sugars is easy. But how to organize them of years in between the origin of suitable conditions into the first living organism has not been worked on the Earth and the oldest known fossils, and we out. So it's very difficult to estimate how frequently

352 THE AMERICAN BIOLOGY TEACHER, VOLUME 51, NO. 6, SEPTEMBER 1989 this might have occurred. My feeling, though, is that Speaking of DNA, it just occurred to me that your it is very frequent, and that the Earthis not unique in famous paper was published the same year as having life." Watson and Crick published their celebrated paper on the double helix-the structure of DNA, the genetic material. What work is presently going on in your laboratory? "Yes, their paper was in the April 25th issue of Na- "I am still studying the synthesis of prebioticorganic ture and mine was in the May 15 issue of Science.I using atmospheres other than methane. compounds, should mention that until then, most biologists the composi- There is considerablecontroversy about thought that the genetic material was protein rather the primitive atmosphere. One of the tion of than DNA. That is why the prebiotic synthesis of problems is that methane and ammonia are decom- amino acids was so striking." posed by ultraviolet light relatively rapidly. So the question is, could we have had that kind of atmo- Finally, what advice can you offer to students who sphere? And if the atmosphere was different, did it are just beginning their college science education still lend itself to organic synthesis? and are thinking about a career in biochemical re- We have been doing experiments using carbon search?

monoxide and carbon dioxide. You can make organic "I think freshmen and sophomores should get a Downloaded from http://online.ucpress.edu/abt/article-pdf/51/6/349/44208/4448946.pdf by guest on 30 September 2021 materialwith these kinds of atmospheres, but only if good background in chemistry and biology. Chem- there is molecular hydrogen around. It's not that istry is very important, because if you don't learn it easy to get molecularhydrogen in large amounts into as an undergraduate, you're probably not going to the atmosphere because it tends to escape from the learn it very well as a graduate student. By the time atmosphere into outer space. Another problem that they're juniors or seniors, students should probably we have been working on in the laboratoryis to try do a little project in a research lab. Since biology is to figure out what primitive RNA was like-RNA is going more and more in a molecular direction, a thought to have preceded DNA as the genetic mate- strong backgroundin chemistry and the ability to be rial, but there was some precursorpolymer to RNA." efficient in the lab are very important."

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MILLER 353