Juan Oró was the first scientist to focus on the synthesis of biological molecules from hydrogen cyanide. This process came to occupy a key role in models for the origin of life, providing a possible piece of the puzzle of how life initially formed on Earth.

The question of life’s origin has engaged the minds of intellectuals since ancient times, but during the twentieth century this subject has moved from the philosopher’s court to the scientist’s laboratory. A major figure in this transformation was the Soviet biochemist Aleksandr Ivanovich Oparin Oparin, Aleksandr Ivanovich , who articulated the paradigm that has guided research in this field: The origin of life can be viewed as a gradual, cumulative process marked by successive stages of increasing complexity. Just as molecular biology has revealed different levels of organization in biochemical systems, the study of primordial life could be approached in a modular fashion, beginning with the synthesis of organic molecules from the primitive atmosphere. Biochemistry;genetic material
Life, origins of
Adenine
[kw]Oró Detects the Formation of Adenine from Cyanide Solution (June, 1960)
[kw]Adenine from Cyanide Solution, Oró Detects the Formation of (June, 1960)
[kw]Cyanide Solution, Oró Detects the Formation of Adenine from (June, 1960)
Biochemistry;genetic material
Life, origins of
Adenine
[g]North America;June, 1960: Oró Detects the Formation of Adenine from Cyanide Solution[06520]
[g]United States;June, 1960: Oró Detects the Formation of Adenine from Cyanide Solution[06520]
[c]Biology;June, 1960: Oró Detects the Formation of Adenine from Cyanide Solution[06520]
[c]Chemistry;June, 1960: Oró Detects the Formation of Adenine from Cyanide Solution[06520]
[c]Science and technology;June, 1960: Oró Detects the Formation of Adenine from Cyanide Solution[06520]
Oró, Juan
Kimball, Aubrey Pierce
Orgel, Leslie Eleazer
Ferris, James Peter

When Juan Oró enrolled in graduate school at the Baylor College of Medicine in 1952, few scientists had a serious interest in the question of how life began. Experiments in several laboratories in the United States and Germany had shown that carbon dioxide could be converted to formaldehyde and other simple products, but no complex molecules had been synthesized. In 1953, however, a second-year graduate student named Stanley L. Miller Miller, Stanley L. at the University of Chicago published a report of amino acids (the constituents of proteins) formed by the action of simulated lightning in a model atmosphere containing methane, ammonia, hydrogen, and water. The use of methane as a carbon source marked a departure from earlier practice, but this mixture had been suggested by Harold C. Urey Urey, Harold C. as representative of the primor-dial atmosphere. Although scientists now believe that the Miller-Urey experiment overestimated the amounts of methane and ammonia on primitive earth, the dramatic synthesis of amino acids stimulated many researchers to enter the field of prebiotic chemistry.

Oró had decided to focus on the origins of life even before Miller published his seminal communication. He had graduated from the University of Barcelona with a degree in chemistry. On his way to Houston, Texas, to attend Baylor University, he stopped in New York to meet a fellow Spaniard named Severo Ochoa Ochoa, Severo . At the age of forty-six, Ochoa was a well-known biochemist who would later win the 1959 Nobel Prize in Physiology or Medicine for his research on the artificial synthesis of polynucleotides. Ochoa encouraged Oró to pursue his goal of developing prebiotic pathways to sugars and related molecules. Oró obtained a position as chemistry instructor at the University of Houston in 1956. His doctoral research on formate metabolism in animals had given him valuable experience in laboratory techniques for biochemical analysis, which were also essential for the research he planned in prebiotic chemistry. Indeed, his early work focused on improvements in these analytical methods. After some initial experiments on the synthesis of amino acids from formaldehyde, Oró turned his attention to cyanide.

Miller had shown that hydrogen cyanide (HCN) was an important intermediate in the synthesis of amino acids during the electric discharge reaction. Other investigators such as Philip Abelson Abelson, Philip , the director of the geophysical laboratory at the Carnegie Institution, had repeated the Miller-Urey experiment using a variety of gas mixtures and confirmed the formation of HCN, leading Abelson and others to conclude that this molecule was probably an important constituent of the primordial atmosphere. While these reactions yielded glycine and other amino acids, they also produced a brown tar that had not been characterized. During a conference in 1959, Abelson and Oró speculated on the origin of this solid residue, which they viewed as extended chains, or “polymers,” of HCN molecules. Oró therefore decided to shift his research to the products that might be formed from cyanide.

Hydrogen cyanide is well known for its acute toxicity, but Oró fortunately had acquired experience while in Spain working with this dangerous substance. During his first studies at Houston, he bubbled HCN into a solution of ammonia to give ammonium cyanide, which then reacted with itself to give more complex molecules. The reaction itself was accompanied by a series of visible changes: from colorless to yellow, then orange, and finally to red, as a dark precipitate began to form. This “alchemist’s brew,” as Oró called it, was heated overnight at just below its boiling point, after which the liquid was analyzed for biological molecules.

The detection technique employed in these studies was paper chromatography, where a tiny drop of an unknown mixture is separated on a long sheet of porous paper that is dipped into a suitable liquid, which carries some components a greater distance than others. When Oró first analyzed the liquid from the cyanide reaction, he found significant amounts of amino acids, along with a very faint trace of adenine, one of the essential bases in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). He subsequently treated the solution with acid and concentrated the product for further characterization: Paper chromatography (using several different solvents and a variety of visualization techniques) provided much stronger evidence for the presence of adenine.

Oró demonstrated that the chemical and physical properties of an authentic sample of adenine were the same as those of the isolated product, thus confirming its identification. This discovery marked the first synthesis of adenine under presumed prebiotic conditions. Oró published his results in the June, 1960, issue of Biochemical and Biophysical Research Communications.

Further characterization of the products formed from ammonium cyanide was carried out by Oró and his graduate student, Aubrey Pierce Kimball. In addition to adenine, they found two imidazole derivatives, one of which was proposed as a precursor to adenine. Oró and Kimball regarded the formation of imidazoles as significant, because such compounds play a catalytic role in biochemistry and because the modern biosynthesis of adenine proceeds through similar molecular species. They also confirmed the formation of amino acids, including glycine, alanine, and aspartic acid, from the heating of ammonium cyanide solutions. The production of adenine and amino acids from a mixture of ammonia and HCN was also verified by a British group under the direction of Roy Markham at the University of Cambridge.

For Oró, the cyanide studies marked the beginning of a long career devoted to understanding the origins of life. A major focus of his subsequent research has been the related molecule—cyanamide—which can be formed from ammonium cyanide by the action of ultraviolet light. Oró and colleagues have utilized cyanamide in the synthesis of oligonucleotides, oligopeptides, and lipids (the building blocks of nucleic acids, proteins, and membranes, respectively). He also served on National Aeronautics and Space Administration (NASA) teams for the analysis of lunar rocks from the Apollo missions and for the interpretation of data from the Martian Viking probes. His contributions have thus extended from the development of prebiotic pathways to the search for life in the universe.

The formation of adenine from a solution of ammonium cyanide marked an important advance in prebiotic chemistry both because of the simplicity of the starting materials and because the reaction yielded amino acids. Since proteins and nucleic acids are essential for modern life, the detection of constituents from both classes of molecules served to heighten interest in cyanide chemistry. Nevertheless, Oró had employed hot temperatures (near boiling) and high concentrations, conditions that many scientists regarded as too restrictive. Leslie Eleazer Orgel at the Salk Institute Salk Institute in California pointed out that even the most optimistic estimate of the cyanide content of the primordial ocean would be well below that used to prepare adenine. A further limitation of Oró’s pathway was that it relied on formamidine (an adduct of HCN and ammonia), which is formed only at high concentrations and is highly unstable in water.

Together with research associates James Peter Ferris and Robert Sanchez Sanchez, Robert , Orgel set out to develop a more general route to adenine starting from HCN. They found that the polymerization of cyanide does indeed occur under more dilute conditions, although a lower limit is eventually reached. In a thorough mechanistic study, they showed that the HCN tetramer (diaminomaleonitrile) is a more likely precursor than the HCN trimer (aminomalononitrile) proposed by Oró. Orgel and Ferris demonstrated that the tetramer can be converted by the action of ultraviolet light into an imidazole derivative that ultimately yields adenine upon further reaction with HCN. Orgel also suggested a clever process by which high concentrations of cyanide could be achieved on primitive earth: The freezing of ponds or lakes could remove much of the water, creating a potent HCN solution in the remaining liquid. The Salk group thus improved on Or’s discovery by demonstrating the synthesis of adenine and its precursors under more natural conditions.

Since 1967, Ferris has led his own research effort devoted to the synthesis of biological molecules from HCN. In his laboratory at Rensselaer Polytechnic Institute in upstate New York, many biochemicals have been detected after the initial products of HCN polymerization are heated in an alkaline solution. The Rensselaer scientists also isolated a diverse array of other molecules that are either components of modern proteins and nucleic acids or are precursors to the constituents of these biopolymers. For example, they found a substance known as orotic acid, which they irradiated with ultraviolet light to form uracil, a major constituent of RNA.

Additional studies of HCN chemistry have been carried out by several other scientists, including Alan Schwartz Schwartz, Alan at the University of Nijmegen in the Netherlands. He and his assistant, Andries Voet Voet, Andries , isolated an HCN pentamer that serves as a precursor to adenine. They also demonstrated that uracil can be formed under conditions that do not require ultraviolet light. The conclusion that can be drawn from these diverse investigations is that HCN can provide a rich source of biological molecules and therefore probably played a significant role in the synthesis of the molecular precursors of early life. The detection of HCN and related compounds in comets and in interstellar space has reinforced the primordial importance of cyanide chemistry. Oró’s pioneering synthesis of adenine from ammonium cyanide thus opened new pathways in the elucidation of the origins of life. Biochemistry;genetic material
Life, origins of
Adenine

• Day, William. Genesis on Planet Earth: The Search for Life’s Beginning. 2d ed. New Haven, Conn.: Yale University Press, 1984. A well-written, nontechnical account of research on the origins of life, with many references to Oró. Includes an extensive list of primary sources.
• Ferris, James P., and David A. Usher. “Origins of Life.” In Biochemistry, edited by Geoffrey Zubay. 4th ed. Dubuque, Iowa: Wm. C. Brown, 1998. A brief summary written by two knowledgeable participants; the level of discussion requires a background in college chemistry.
• Luisi, Pier Luigi. The Emergence of Life: From Chemical Origins to Synthetic Biology. New York: Cambridge University Press, 2006. Comprehensive overview and detailed analysis of the development of organic life from inorganic matter. Bibliographic references and index.
• Oparin, A. I. The Origin of Life. 2d ed. New York: Dover, 1953. First published in Russian in 1936, this translation provided many English readers with their first view of Oparin’s model. The opening chapters provide a succinct history of ideas on the origin of life.
• Orgel, L. E. The Origins of Life: Molecules and Natural Selection. New York: John Wiley & Sons, 1973. Although somewhat dated, this book offers an introduction and selected bibliography for the advanced high school student or general reader.
• Oró, J. “Prebiological Chemistry and the Origin of Life: A Personal Account.” In Reflections on Biochemistry, edited by A. Kornberg, B. L. Horecker, and L. Cornudella. New York: Pergamon Press, 1976. An autobiographical essay with emphasis on Oró’s scientific work.
• Raymo, Chet. Biography of a Planet: Geology, Astronomy, and the Evolution of Life on Earth. Englewood Cliffs, N.J.: Prentice Hall, 1984. A highly illustrated survey, ranging from the origin of the solar system to early human evolution, with a brief discussion of prebiotic synthesis. Appropriate for high school students.

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