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IN MEMORIAM
Stanley L. Miller
Professor Emeritus of Chemistry and Biochemistry
UC San Diego
1930 – 2002
Stanley L. Miller, the father of prebiotic chemistry – the synthetic organic chemistry that takes place under natural conditions in geocosmochemical environments – passed away on May 20, 2007 at age 77 after a lengthy illness. Stanley was known world-wide for his experimental demonstration of the synthesis of organic compounds with relevance to the origin of life. On May 15, 1953, while Miller was a graduate student of Harold C. Urey at the University of Chicago, he published a short paper in Science on the prebiotic synthesis of amino acids under simulated early Earth conditions. This paper and the experiment it described had a tremendous impact and immediately transformed the study of the origin of life into a respectable field of inquiry.
Stanley Lloyd Miller was born in March 7, 1930, in Oakland, California, the second child (the first was his brother Donald) of Nathan and Edith Miller, descendants of Jewish immigrants from Belarus and Latvia. Both parents attended the University of California, Berkeley (UC Berkeley), where they met. Stanley’s father became a very successful attorney who was appointed a Deputy District Attorney in 1927 by Earl Warren, who was then the District Attorney in Alameda County and who eventually became the 30th Governor of California and the 14th Chief Justice of the United States Supreme Court.
From an early age Stanley was an eager learner and avid reader. He easily advanced through Oakland High School, where he was known as “a chem whiz”. He also had an interest in the natural world and became involved in the Boy Scouts, achieving the level of an Eagle Scout. Stanley particularly liked Boy Scout summer camp because he could get away from people, enjoy the beauty of nature, and read undisturbed. After he returned to California in 1960 as a faculty member of the new University of California, San Diego campus he often spent summers in the Sierra Nevada Mountains.
Like his parents before him, Stanley as well as his older brother Donald, went to UC Berkeley for their undergraduate studies. Because his brother had chosen to study chemistry, Stanley decided to follow in his footsteps, mainly because he knew his brother would help him if had trouble with his courses. He had taken most of the undergraduate chemistry classes by the end of his junior year and as a senior took graduate courses and carried out a senior thesis research project. Stanley did extremely well at UC Berkeley and his first two published papers were based on his undergraduate research.
When Stanley decided to go to graduate school, he consulted with several of his professors, who came up with a short list of schools they recommended. At the top of the list were the University of Chicago and the Massachusetts Institute of Technology. He applied to both, but after receiving a telegram from the University of Chicago in February of 1951 notifying him of his acceptance, including an offer of a teaching assistantship, he quickly accepted. Stanley graduated from UC Berkeley in June of 1951 and then headed for Chicago.
During his first semester, in the fall of 1951, Stanley went to a seminar in which Professor Harold C. Urey presented his ideas about the origin of the solar system and the chemical events associated with this process. One of the points that Urey made was that the atmosphere of the primitive Earth was much different from the modern atmosphere and likely consisted of a highly reducing mixture of methane, ammonia, hydrogen sulfide and hydrogen. Urey further suggested that with such an atmosphere it might be possible to synthesize organic compounds that in turn could have provided the raw materials needed for the emergence of life. This seminar obviously left a lasting impression on Stanley because he could still remember aspects of the lecture many years later.
At the start of his second year at Chicago, Stanley began thinking about a suitable Ph.D. thesis topic. He approached Urey in September of 1952 about the possibility of doing a prebiotic synthesis experiment using a reducing gas mixture. Urey was not very enthusiastic. He felt, with some justification, that graduate students should do only those experiments that had a reasonable chance of working, rather than taking a leap into the unknown. He suggested instead that Miller work on determining the amount of the element thallium in meteorites, a safe and pedestrian topic. Urey's reasoning was that the abundance of thallium seemed higher in the crust than in meteorites, but Urey felt the data were too inadequate to confirm this, and the issue could be resolved only with further careful analyses. But Miller was persistent about the prebiotic synthesis project. Urey finally relented and agreed to let him try some experiments, but specified that there must be signs of success within a year or the project should be abandoned.
The first challenge was to design an apparatus for the experiment. Some sort of high-energy input to induce chemical reactions was required. Miller knew that chemists had been experimenting with electric sparks in gas mixtures since the pioneering work in the 18th century by Lord Cavendish, who showed that the action of a spark discharge in air results in the production of nitrous acid. However, it appeared that no one had thought about how this might relate to prebiotic syntheses and the origin of life. Stanley realized that such discharges were probably common on the early Earth. The atmosphere at the time must have been subject to extensive lightning, along with corona discharges, and lightning would also have been associated with volcanic eruptions that were common on the primitive Earth. In the laboratory, a spark discharge simulating these processes could be easily made using a simple commercially available Tesla coil.
The eventual apparatus that was designed was meant to simulate the ocean-atmosphere system on the primitive Earth. The apparatus consisted of two glass flasks connected by glass tubing. One flask contained only water, while the other had electrodes and contained the reduced gases methane, ammonia and hydrogen (most of the ammonia gas dissolved into the water flask during the experiment). One tube directly connected the water flask to the gas/electrode flask. The other tube was U-shaped and connected the two flasks. At the top of the U-tube was a condenser that acted to condense water from the gas flask, allowing it to flow back into the water flask. Water vapor produced by heating the water flask would be like evaporation from the oceans, and as it mixed with the reduced gases, it would mimic a water vapor-saturated primitive atmosphere. The condenser returned any compounds produced in the gas phase back into the water, much as rain and river discharges transport compounds from the atmosphere into the oceans.
Intriguing results were produced almost as soon as Stanley began the experiments in the fall of 1952. Although the methods available to Stanley were crude in comparison with contemporary analytical tools, he was able to demonstrate that glycine could be detected after only two days of sparking the gaseous mixture. After repeating the experiment and sparking the gas mixture for a whole week, he noticed that the inside of the sparking flask was coated with a dark, oily material and that the water had a yellow-brown color. When two-dimensional paper chromatography with ninhydrin detection was used to analyze the water solution, the glycine spot was much more intense, and spots corresponding to several other amino acids were also detected.
When Miller showed the results to Urey, they decided that it was time to write a manuscript describing the experiment and submit this for publication, preferably in a leading journal. Stanley completed a draft of the manuscript and asked Urey for his comments, which he promptly provided. Urey also declined Stanley's offer to be co-author because otherwise Stanley would receive little or no credit. Urey then contacted the editors of Science and asked them to quickly review the manuscript and publish it as soon as possible. The manuscript was submitted to Science on February 10, 1953 and published 3 months later.
Although Stanley’s experiments and publication of the Science paper laid the foundation for the field of prebiotic synthesis, further work was needed to validate the results. Thus, Miller started to refine the details and the analytical aspects of the experiment. The first order of business was to identify the amino acids more rigorously. He used melting point determinations, which at that time were considered to be the most conclusive way to identify organic compounds. These tests confirmed the identities of the amino acids Miller had found earlier, and also showed that an even wider variety of amino acids had been made than he had first thought. At the end of all this painstaking work, nine different amino acids had been positively identified, and a host of others whose identity was uncertain were also shown to be present. Some of the ones that had been identified, such as glycine, alanine and glutamic acid, are found in proteins, but others, such as -alanine, are not.
Amino acids were not the only compounds produced in the discharge apparatus. Miller found another class of closely related compounds called hydroxy acids. The simplest of these was glycolic acid, the analog of glycine. The hydroxy acid relative of alanine, lactic acid, was also found, as were the hydroxy acids corresponding to many of the other amino acids that had been produced in the experiment. This led Stanley to suggest that the amino acids had been synthesized by the Strecker reaction, which had been discovered in 1850. In this synthesis, hydrogen cyanide reacts with aldehydes and ketones in the presence of ammonia to first form amino nitriles that when hydrolyzed yield amino acids. By painstakingly carrying out a time-series sampling of the water solution from the spark discharge apparatus, Stanley was able to demonstrate that cyanide and aldehydes were produced during the course of the experiment, thus supporting the surmise of a Strecker-based synthesis.
After Miller earned his Ph.D. in Chemistry in 1954, he moved to the California Institute of Technology, where he was an F.B. Jewett Fellow from 1954-1955. During this period, he worked on determining the mechanisms involved in the amino and hydroxy acid synthesis. Stanley then joined the Department of Biochemistry at the College of Physicians and Surgeons, Columbia University, where he stayed until he was appointed in 1960 the first Assistant Professor in the Department of Chemistry at the new University of California, San Diego. He was quickly promoted to Associate Professor in July of 1962 and to Professor in July of 1968. Stanley retired from active service on June 30, 1994, but continued to run his research program and act as a mentor for graduate and undergraduate advisor when he returned as a Research Professor from October 1995 to September 1997. During this period, he mentored his last graduate student, Henderson James Cleaves, who received his Ph.D. in 2001.
He was a conscientious citizen of the Department of Chemistry and Biochemistry, teaching laboratory courses in analytical chemistry and a course on Biochemical Evolution, planning the construction of the Undergraduate Sciences Building (now York Hall), serving as Chair of the Undergraduate Curriculum Committee, where he established a forward thinking major in Environmental Chemistry, and directing the research of a dedicated group of undergraduate and graduate students.
Miller continued to carry out research in various aspects of prebiotic chemistry and the origin of life throughout his career. His main interest was not only the synthesis of key biochemical components under plausible conditions on the early Earth and elsewhere, but also the question of their stability in geocosmochemical environments. Stanley was particularly interested in how the transition from simple abiotic chemistry to biochemistry took place and in the nature of the first entity that could undergo self-sustaining replication, however imperfect. This was reflected in his experimental analysis of the stability of RNA components; the prebiotic synthesis of alternative nucleobases that could substitute for those present in present-day RNA and DNA; and the synthesis under possible prebiotic conditions of the subunits of peptide nucleic acids, which are considered by some to be the prototype molecular entity capable of self-sustained self-replication.
Although Stanley is best known for his work in prebiotic chemistry, he also made significant contributions in other fields. He was interested in gas clathrates (hydrates), icy solids made of water molecules that contain “cages” in which small gas molecules can be entrapped. He published several papers on the occurrence of hydrates on Mars and in Antarctic ice, as well as their possible role in anesthesia. In his research on the clathrate of air, he predicted it would form at the depth where gas bubbles in the Antarctic ice sheet disappeared. Stanley proposed the name for this natural occurring air clathrate "Craigite" in honor of his UCSD colleague, friend, and fellow Urey graduate student Harmon Craig. It was soon jokingly noted by various colleagues that when “Craigite” melts at atmospheric pressure, it spontaneously explodes to hot gas and water, in reference to Craig’s sometime volatile personality. Others soon confirmed the presence of “Craigite” in Antarctic ice.
In addition, it was only logical that with his research into the origin of life, Stanley was also interested in the possibility of life beyond Earth, in particular on Mars. Stanley considered amino acids to be the best compounds to detect for possible evidence of either prebiotic chemistry or life beyond Earth because of their ubiquitous role in terrestrial biochemistry and the ease by which they could be synthesized under prebiotic conditions. He received a grant from NASA to develop a miniaturized extraction system and an amino acid analyzer that could be deployed on a future mission to the red planet. Stanley was able to construct a functioning prototype of the instrument that was about the size of a shoebox (compare this to the standard laboratory amino acid analyzer, which at the time was about the size of a refrigerator). With prototype instrumentation in hand, Stanley decided to try to use it to answer the question of life beyond Earth once and for all – he proposed the amino acid instruments as part of the experimental package for the NASA Viking missions that landed two spacecraft on the surface of Mars in 1976. He was disappointed when he learned that his instrument was not selected, and in his final report to NASA Stanley mentioned that he hoped that something along the lines of his proposed design might someday fly to Mars.
Although Miller was a dedicated scientist, he also had many outside interests and activities. He was an avid traveler and he documented his travels with slides, which he eagerly showed to his friends when he returned home. His 1957 trip to Moscow to attend the First International Conference on the Origin of Life was his first trip to Europe and was probably his first on an airplane. He kept a detailed record of the people he met, the food he sampled, and the various places he visited, a practice he would follow in most of his subsequent trips. Stanley was also a railroad enthusiast and especially liked steam locomotives, which was perhaps a carryover from the times he traveled to Chicago and later New York when train transportation was often the only affordable means of travel. Miller frequently went on trips in Europe and elsewhere by train, including taking the Trans-Siberian railroad from Moscow to Vladivostok, as well as train trips across India and to various areas in Japan. After traveling in India, Miller took a bus through the Khyber Pass in the Hindu Kush Mountains between Pakistan and Afghanistan. He then traveled on to Iran and other places in the Middle East, which today is not a very feasible or recommended trip.
Miller especially enjoyed riding his bicycle and often rode from his home to UCSD as well as riding to various regions of San Diego County. One of his favorite activities was to take bicycling tours in Europe that involved staying at hotels with outstanding restaurants nearby. He felt he could indulge himself with excellent meals because he would get plenty of exercise the next day. Miller often returned in the summer to the Evergreen Lodge just outside Yosemite National Park, where he would ride his bicycle to various places in the area.
Miller went on several expeditions with colleagues from the Scripps Institution of Oceanography. He traveled in 1966 and 1967 to Australia’s Great Barrier Reef and to the Brazilian Amazon River to take part in research onboard the RV Alpha Helix. He also traveled across South Africa, Kenya and Tanzania with one of us (JLB) during research trips to collect samples for a study of the geochemistry of amino acids in fossil bones. The places visited in Tanzania included Olduvai Gorge, where we were hosted by Mary Leakey.
Besides these activities Miller enjoyed opera. He read extensively on the history of World War II, possibly because part of his family suffered greatly during this period. He also was an avid reader of books on Winston Churchill and maritime warfare.
Miller was awarded numerous honors throughout his career. He was president of the International Society for the Study of the Origin of Life (ISSOL) from 1986 to 1989, and the Society awarded him the Oparin Medal in 1983 for his work in the field. He was selected as an Honorary Councilor of the Higher Council for Scientific Research of Spain in 1973. Miller was elected to the U. S. National Academy of Sciences in 1973. In 2009, his 1953 paper in Science was selected by the Division of the History of Chemistry of the American Chemical Society for one of their Chemical Breakthrough awards. Miller belonged to Sigma Xi and Phi Beta Kappa and was a member of the American Chemical Society, the American Association for the Advancement of Science, and the American Society of Biological Chemists.
Jeffrey L. Bada, Chair
Charles L. Perrin
Patricia A. Jennings