MILLER, STANLEY LLOYD

(b. Oakland, California, 7 March 1930; d. National City, California, 20 May 2007),

chemistry, prebiotic chemistry, origin of life, astrobiology.

Miller’s pioneering work was instrumental in the establishment of the scientific field devoted to the study of the emergence of life on Earth. In a series of breakthrough experiments in the early 1950s, he demonstrated for the first time the synthesis of biologically relevant organic compounds from simple building blocks under physical and chemical conditions presumed to exist on the primeval Earth. Since then, together with numerous colleagues and students, Miller has investigated the possible steps and chemical compounds involved in the emergence of life. His other research interests include the natural occurrence on Earth and other parts of the solar system of clathrates, or gas hydrates, a class of crystalline solids in which water molecules form cagelike structures around low-molecular-weight gases, most commonly methane. In the 1960s, Miller suggested a mechanism of general anesthetics with reference to possible clathrate hydrate formation.

Family Background and Professional History . Miller was born in Oakland, California, to Nathan Harry Miller and Edith Eileen Levy. His father was a lawyer and served as a deputy and later assistant district attorney in Oakland, working under Earl Warren, then the district attorney for Alameda County and later chief justice of the U.S. Supreme Court. His mother had been a teacher before marrying and later a homemaker. Miller’s father, born in then czarist Russia, now Belarus, was the first in his large, Jewish immigrant family to go to college. Both Miller and his brother were encouraged to become lawyers or doctors. Miller’s older brother Donald chose chemistry instead and Stanley followed suit, both joining the University of California (UC) at Berkeley, whose Department of Chemistry was among the best in the nation. Donald

received a PhD from the University of Illinois and spent most of his career as a senior chemist at the Lawrence Livermore National Laboratory.

Stanley Miller, who was an avid reader, attended public schools in Oakland and his decision to pursue a career in science was influenced both by his brother’s choice and his own belief in the importance of science for society. Miller received a BS in chemistry from UC Berkeley in 1951 and a PhD, under the mentorship of Harold Urey, from the University of Chicago in 1954. In 1955 he was a F. B. Jewett Fellow at the California Institute of Technology, and from 1955 to 1960 a postdoctoral fellow, instructor, and assistant professor in the Department of Biochemistry, College of Physicians and Surgeons, Columbia University. Urey, who moved to the University of California, San Diego (UCSD), in 1958 and his colleagues, being impressed by Miller’s outstanding work and achievements, invited him in 1960 to join the Chemistry Department. Miller was instrumental in shaping the new San Diego campus and its curriculum, becoming a full professor in 1968.

As an acknowledgment of his eminent contribution to the establishment of the origin-of-life field, Miller was

the first scientist working in this area to be elected (in 1973) to the National Academy of Sciences. In 1983 he received the Oparin Medal, the highest recognition of the International Society for the Study of the Origin of Life, and was the president of this society from 1986 to 1989. He was an honorary councilor of the Higher Council for Scientific Research of Spain and a member in the Phi Beta Kappa and Sigma Xi organizations.

Following a series of strokes since 1999, Miller died in a hospital in National City, south of San Diego, at age 77. His scientific legacy was commemorated in numerous obituaries in the scientific and general press.

The Miller-Urey Experiment . In the fall of 1951, shortly after he began his graduate studies at the University of Chicago, Miller was captivated by a lecture given by Nobel laureate chemist and physicist Harold Urey. Based on his theory of the origin of solar systems, Urey suggested that the primordial terrestrial atmosphere was hydrogen rich, that is, of a reducing nature. He emphasized the relevance of the atmosphere’s constituents to the synthesis of organic molecules and to the origin of life, urging experimental study of these issues (Urey, 1952).

Miller was engaged at that time with his thesis advisor, Edward Teller, the father of the hydrogen bomb, in an attempt to elucidate the mechanism of the synthesis of chemical elements in stars. However, this work did not show progress and when Teller left the University of Chicago abruptly to establish the Radiation Laboratory at the University of California, the not yet twenty-three-year-old Miller approached Urey. Overcoming his initial reluctance, Urey agreed in the fall of 1952 to let Miller perform an experiment simulating early Earth conditions in order to examine prebiotic chemical reactions and their products.

Unbeknownst to Urey, and brought to his attention only after his 1951 talk, his ideas on the nature of the early atmosphere matched the groundbreaking origin-of-life theory formulated in the 1920s and 1930s by the Russian biochemist Alexander Oparin. Oparin’s ideas, together with a similar, though more limited, theoretical elaboration by the British geneticist and biochemist J. B. S. Haldane, were later referred to as the Oparin-Haldane hypothesis. Contending that the synthesis of organic compounds from constituents of the ancient atmosphere was a crucial step toward life, Oparin and Haldane further suggested that the chemical evolution of these simple organic molecules into more complex ones took place in the primitive ocean, forming the “primordial soup.” Since an atmosphere rich in oxygen, similar to the present one, decomposes organic material, all these stages were proposed to be made possible by the existence of an atmosphere constituted of the reducing gases, ammonia (NH₃), methane (CH₄), free hydrogen (H₂), and water vapor.

By hypothesizing the emergence of the first organisms from organic molecules synthesized in the prebiotic environment, Oparin and Haldane rejected the then-prevailing autotrophic notion that organic matter was built by early life from carbon dioxide and water. Adopting Oparin and Haldane’s conception, the ensuing Miller-Urey experiment differed from previous attempts (conducted with no connection to the origin-of-life question) to synthesize organic compounds within the autotrophic tradition. Furthermore, by simulating a reducing atmosphere Miller’s procedure differed from several experiments performed in the early 1950s, with the origin of life in mind, in which carbon dioxide instead of methane was used and which did not produce biologically relevant organic compounds in high yield.

Miller built a system of glass flasks and tubes in which water vapor was obtained by boiling the “ocean” in a reservoir of water. The vapor was transferred to a gas mixture containing methane, ammonia, and hydrogen, simulating the primordial atmosphere. Urey and Miller hypothesized that ultraviolet light and electric discharges might have been the principal primordial sources of energy in the synthesis of organic compounds. For technical and theoretical reasons electric discharges, simulating lightning, were chosen and applied via electrodes attached to the “atmosphere vessel.” The continuous discharge caused the gases to interact and the products were then condensed and moved back to the “ocean,” where some of them were dissolved.

In November 1952, Miller applied the described procedure to perform his most elaborate experiment. Analysis of the reaction products revealed that about 10 percent of the available carbon was converted into organic compounds, about 2 percent of which were amino acids, the building blocks of proteins. Miller determined that hydrogen cyanide (HCN) and formaldehyde (H₂ CO) were the major organic products in the gas mixture and their interaction in the “ocean” led to the synthesis of amino acids. The results, published in the journal Science on 15 May 1953, caused great excitement in the scientific community, as well as in the popular press, and were later repeated and confirmed by other investigators.

Significantly, the results were not statistically random: only a small number of biologically relevant organic compounds in high yields were produced in the experiment out of the vast number of potential organic substances. Glycine and alanine, the most common amino acids in proteins, were the major products (Lazcano and Bada, 2003). Moreover, in work performed by Miller and other researchers in the 1970s it was found that the same amino acids and in the same relative quantities were obtained when the content of meteorites that reached Earth were analyzed, particularly the Murchison meteorite that fell in Australia in 1969. Since meteorites are considered to be relics of the formation of the solar system, their organic content could indicate that chemical processes similar to the Miller reactions were common in the solar system, including the prebiotic Earth.

In experiments by Miller and others that followed in the 1950s and 1960s, various mixtures of reducing gases and sources of energy were used to yield amino acids and other organic molecules. The chemist Juan Oró achieved the synthesis of the nitrogenous base adenine, an important component of the nucleic acids, DNA and RNA.

Miller’s Further Contributions . Miller’s groundbreaking prebiotic synthesis of organic compounds was based on the notion of a primordial reducing atmosphere. Oparin and then Urey founded this notion on the discovery of CH₄ and NH₃ in the atmospheres of Jupiter, Saturn, Uranus, and Neptune, and on the then-accepted assumption that Earth was formed from a hydrogen-rich dust cloud. Later models of the origin of the early atmosphere emphasized the volcanic release of gases from Earth’s mantle, following the impact of meteorites and other bodies on Earth’s surface during its formation. A gradually emerging picture depicts a complex atmosphere, resulting both from external impacts and internal processes in Earth’s mantle. Carbon dioxide (CO₂), carbon monoxide (CO), nitrogen (N₂), water, methane, and hydrogen were probably all present in varying proportions.

Though the nature of the early atmosphere is still an unsettled question, explored through experiments and novel theoretical models, Miller went on to investigate the modified conception of the primordial atmosphere in his later work. Among his studies conducted since the 1980s, Miller achieved, in the early 2000s, the synthesis of amino acids and nucleic acid bases in a gas mixture that contained CO, CO₂, N₂, and H₂ O, using high-energy protons as a high-energy source required in less reducing conditions.

Another related, and as yet unsettled, question pertains to the source of organic compounds on the early Earth. Based on the discovery of a variety of organic molecules in outer space, and on the analysis of the contents of comets and meteorites, it is widely accepted that massive amounts of organic materials and water were delivered to Earth by impacting bodies at least during its first half billion years. Many investigators regard this external delivery as the only source for organic material. Miller and others view it as a possible addition to organic synthesis that was carried out on Earth. Obviously, the relative importance of these two sources depended on the relative abundance of reducing gases in the atmosphere.

The site on Earth where life might have emerged is among the most contentious issues in the origin-of-life community. Since the late 1970s, an alternative research program contesting the primordial “soup” notion suggests the synthesis of bioorganic molecules and the emergence of life at the vicinity of hydrothermal vents on the ocean floor. According to this theory, mineral surfaces, reducing gases released from the ocean crust, and the availability of chemical energy in these sites provided a more suitable environment for organic synthesis and the emergence of life than the ocean.

Miller has long rejected the hydrothermal-vents hypothesis, claiming that the high temperatures of the vents are destructive to organic molecules. In a series of studies performed since the late 1980s, Miller showed that higher temperatures are not compatible with both amino acid and nucleic acid bases. In experiments performed in the 1990s and 2000s he extended the ocean notion and showed that prebiotic material could have been concentrated on beaches and drying lagoons that provide abundant mineral surfaces necessary for polymerization. However, this does not exclude a role for the ocean’s soup as a source for the required building blocks.

The hydrothermal-vent-and-temperature debate led Miller to study the time window during which life could have emerged. He referred to the fact that the entire ocean passes through the deep-sea vents every ten million years, destroying in this process all the dissolved organic components. In various publications in the 1990s Miller thus claimed that living systems had to emerge within a geologically short period, maybe not more than ten million years, compatible with the destruction rate of their components. The general trend of narrowing the time window is a radical departure from the older notion of billions of years during which life could have emerged due to a “lucky accident.”

Miller’s Work on the RNA and Pre-RNA Worlds . Following the famous Watson-Crick discovery of the double-helical structure of DNA (published one month before the Miller 1953 paper) and the consequent rise of molecular biology, the origin-of-life problem began to be formulated in terms of genetic material, protein enzymes, and their interaction. For Miller, the most fundamental question facing researchers was the nature of the first genetic material that could have replicated, mutated, and evolved. Opinions on this question differ between the metabolic and genetic points of view, implicitly referred to by Oparin and Haldane, respectively, in the 1920s and 1930s. These two traditions that came into full bloom following the development of the origin-of-life field in the 1960s emphasize different aspects of the conception of life: “geneticists” view life first and foremost as a self-replicating molecular entity; “metabolists,” as an organized system of interacting molecules maintaining its stability through metabolism. Miller has always fiercely opposed the metabolists, rejecting their contention that the early stages of natural selection and evolution in the emergence of life could have depended on the reproduction of a multimolecular, metabolizing system instead of the replication of a genetic molecule (Fry, 2000).

Miller, together with Leslie Orgel, a leading origin-of-life scientist, and many other “geneticists” became convinced that a watershed in life’s emergence was the RNA-world—a hypothetical prebiotic stage in which RNA molecules functioned both as genetic material and as catalysts. The possibility of such dual function was indicated following the discovery in the 1980s of RNA enzymes, later called ribozymes. The RNA-world theory, strengthened by the discovery of ribozymes, seems to suggest a solution to a basic challenge facing the study of the origin of life: the chicken-and-egg relationship between nucleic acids and proteins, which depend on each other for their synthesis and function.

However, based on Miller’s and other scientists’ work, the RNA-world could not have been the first chemical “world” to emerge, owing to the complexity of RNA and its constituents. Since the early 1990s, Miller and colleagues began searching for a pre-RNA world, constituted of molecules that were easier to synthesize prebiotically, that could have replicated, and that could have later transformed into RNA.

Of the RNA nitrogen bases, purines are synthesized prebiotically more readily than pyrimidines. Miller demonstrated for the first time in the 1990s that high yields of the two pyrimidine bases, uracil and cytosine, can be achieved not in a dilute solution but under drying conditions. He also produced urazole, a modified uracil in which a five-membered ring replaced the six-membered one. Due to its chemical properties, urazole could have been a possible precursor of uracil. Another line of study involved the production of substituted uracils, to which various amino acids were attached. Assuming that such molecules could have been part of ribozymes, they would have greatly enhanced the catalytic activities of RNA enzymes.

Following numerous experiments under prebiotic conditions, Miller became convinced that ribose, the sugar component in RNA building blocks, could not have played a role in the first genetic polymers. Without enzymes, ribose cannot be synthesized in adequate quantity and purity. Moreover, both ribose and other sugars are highly unstable in aqueous solutions, even at low temperatures. Thus, Miller and others began experimenting with alternatives to the present-day ribose-phosphate backbone of RNA. Among the most serious candidates, originally suggested by Peter E. Nielsen, is peptide-nucleic-acid (PNA), a polymer that has a proteinlike backbone to which nitrogen bases are attached. Miller has shown that the units composing the PNA backbone can be easily synthesized in mildly reducing conditions. They can be concentrated and polymerized under conditions that simulate drying beaches and lagoons.

Miller the Exobiologist . From its inception, Miller’s research on the origin of life was embedded in the wider context of the search for life on other planets. In the wake of the 1953 experiment, the astronomer Carl Sagan described his mission in science as extending Miller’s results to astronomy. The results of the Miller-Urey experiment were interpreted in the 1950s and at later times as indicating the possibility of bioorganic synthesis in the primordial solar system and on other solar-system planets. After the founding of the National Aeronautics and Space Administration (NASA) in 1958, the young Miller was among the main contributors to the establishment of the field of “exobiology,” later to be called astrobiology. Several of Miller’s later experiments lent credence to the hypothesis that the potential for prebiotic chemistry exists beyond Earth. He and colleagues have shown that ade-nine, glycine, and alanine can be produced in solutions frozen for years, made of materials similar to the atmospheric constituents of the 1953 experiment. It seems that such synthesis might be possible under conditions prevalent on Jupiter’s moon, Europa, and possibly on other jovian moons. In 1992, NASA established a “virtual” research center, NSCORT (NASA Specialized Center of Research and Training), including the research groups of Miller, Leslie Orgel, Jeffrey Bada, Gustaf Arrhenius, and Gerald Joyce at UCSD and the Scripps Institute of Oceanography. NSCORT investigators have since been active in the study of the origin of life on Earth and beyond.

Miller’s Legacy . Creationists, strongly denounced by Miller for promoting ignorance about science, often rely on the empirical debates among origin-of-life scientists over specific prebiotic scenarios to discredit the very study of the emergence of life. However, in distinction to ongoing scientific controversies, contentions that life could have emerged on Earth only through a supernatural intervention are antiscientific in nature. Clearly, the empirical details of both the Oparin-Haldane hypothesis and the Miller experiments were reflections of their corresponding 1930s and 1950s scientific contexts that later underwent some changes. Nevertheless, the fundamental evolutionary philosophical and theoretical assumptions underlying Miller’s endeavor continue to guide origin-of-life research.

Most importantly, Miller’s 1953 study helped to establish a new experimental field by opening avenues of research into the origin of life. His work since 1953, embodying both the achievements and the open questions still facing the field, attests to the significance of his scientific legacy. Already as a young scientist, Miller was noted for his extraordinary persistence in pursuing the most difficult scientific problems. It was this persistence, in addition to his other professional assets, that accounted for Miller’s groundbreaking contributions to the establishment and development of the study of the emergence of life on Earth.

BIBLIOGRAPHY

A Web site with an extensive list (though not covering all the years) of Miller’s references is http://exobio.ucsd.edu/miller.htm.

WORKS BY MILLER

“A Production of Amino Acids under Possible Primitive Earth Conditions.” Science 117 (1953): 528–529.

With Harold C. Urey. “Organic Compound Synthesis on the Primitive Earth.” Science 130 (1959): 245–251.

“The Atmosphere of the Primitive Earth and the Prebiotic Synthesis of Amino Acids.” Origins of Life 5 (1974): 139–151. On Murchison meteorite.

“Clathrate Hydrates in the Solar System.” In Ices in the Solar System, edited by J. Klinger, 59–78. Dordrecht, Netherlands: Reidel, 1985.

With Antonio Lazcano. “How Long Did It Take for Life to Begin and Evolve to Cyanobacteria?” Journal of Molecular Evolution 39 (1994): 546–554.

With Antonio Lazcano. “The Origin of Life—Did It Occur at High Temperatures?” Journal of Molecular Evolution 41 (1995): 689–692.

With Michael P. Robertson. “Prebiotic Synthesis of 5-Substituted Uracils: A Bridge between the RNA World and the DNA-Protein World.” Science 268 (1995): 702–705.

With Rosa Larralde and Michael P. Robertson. “Rates of Decomposition of Ribose and Other Sugars: Implications for Chemical Evolution.” Proceedings of the National Academy of Sciences of the United States of America 92 (1995): 8158–8160.

“From Primordial Soup to Prebiotic Beach.” Interview by Sean Henahan conducted in October 1996. Available from http://www.accesexcelence.org/WN/NM/miller.html.

With Matthew Levy, Karen Brinton, and Jeffrey L. Bada. “Prebiotic Synthesis of Adenine and Amino Acids under Europa-like Conditions.” Icarus 145 (2000): 609–613.

With Kevin E. Nelson and Matthew Levy. “Peptide Nucleic Acids rather than RNA May Have Been the First Genetic Molecule.” Proceedings of the National Academy of Sciences of the United States of America 97 (2000): 3868–3871.

With Kevin E. Nelson, Michael P. Robertson, and Matthew Levy. “Concentration by Evaporation and the Prebiotic Synthesis of Cytosine.” Origins of Life and Evolution of the Biosphere 31 (2001): 221–229.

With Miyakawa Shin, Hiroto Yamanashi, Kensei Kobayashi, et al. “Prebiotic Synthesis from CO Atmospheres: Implications for the Origins of Life.” Proceedings of the National Academy of Sciences of the United States of America 99 (2002): 14628–14631.

OTHER SOURCES

Fry, Iris. The Emergence of Life on Earth: A Historical and Scientific Overview. New Brunswick, NJ: Rutgers University Press, 2000.

Lazcano, Antonio, and Jeffrey L. Bada. “The 1953 Stanley Miller Experiment: Fifty Years of Prebiotic Organic Chemistry.” Origins of Life and Evolution of the Biosphere 33 (2003): 235–242.

Urey, Harold C. “On the Early Chemical History of the Earth and the Origin of Life.” Proceedings of the National Academy of Sciences of the United States of America 38 (1952): 351–363.

Iris Fry