Stanley Miller and the Quest to Understand Life's Beginning

Thursday 26th July saw the launch of SciLogs.com, a new English language science blog network. SciLogs.com, the brand-new home for Nature Network bloggers, forms part of the SciLogs international collection of blogs which already exist in German, Spanish and Dutch. To celebrate this addition to the NPG science blogging family, some of the NPG blogs are publishing posts focusing on ?Beginnings.? Participating?in this cross-network blogging festival is nature.com?s Soapbox Science blog, Scitable?s Student Voices blog and bloggers from SciLogs.com, SciLogs.de, Scitable and Scientific American?s Blog Network. Join us as we explore the diverse interpretations of beginnings ? from scientific examples such as stem cells?to first time experiences such as publishing your first paper. You can also follow and contribute to the conversations on social media by using the #BeginScights hashtag. ? Bora

In the spirit of ?beginnings,? I?m serving up this lightly edited excerpt from The End of Science (1996) on life?s origin, which?tellingly?has not been rendered obsolete by any subsequent research.? John Horgan

One of the 20^th century?s most diligent and respected origin-of-life researchers is Stanley Miller. He was a 23-year-old graduate student in 1953 when he sought to recreate the origin of life in a laboratory. He filled a sealed glass apparatus with a few liters of methane, ammonia and hydrogen (representing the atmosphere) and some water (the oceans). A spark-discharge device zapped the gases with simulated lightning, while a heating coil kept the waters bubbling. Within a few days, the water and gases were stained with a reddish goo. On analyzing the substance, Miller found to his delight that it was rich in amino acids. These organic compounds are the building blocks of proteins, the basic stuff of life.

Miller?s results seemed to provide stunning evidence that life could arise out what the British chemist J.B.S. Haldane had called the ?primordial soup.? Pundits speculated that scientists, like Mary Shelley?s Dr. Frankenstein, would shortly conjure up living organisms in their laboratories and thereby demonstrate in detail how genesis unfolded. It hasn?t worked out that way. In fact, almost 40 years after his original experiment, Miller told me that solving the riddle of the origin of life had turned out to be more difficult than he or anyone else had envisioned. He recalled one prediction, made shortly after his experiment, that within 25 years scientists would ?surely? know how life began. ?Well, 25 years have come and gone,? Miller said drily.

After his 1953 experiment, Miller had dedicated himself to the search for the secret of life. He developed a reputation as both a rigorous experimentalist and a bit of a curmudgeon, someone who is quick to criticize what he feels is shoddy work. When I met Miller in 1990 in his office at the University of California at San Diego, where he is a professor of biochemistry, he fretted that his field still has a reputation as a fringe discipline, not worthy of serious pursuit.

?Some work is better than others,? he said. ?The stuff that is awful does tend to drag it down. I tend to get very upset about that. People do good work, and then you see this garbage attract attention.? In fact, Miller seemed unimpressed with any of the current proposals on the origin of life, referring to them as ?nonsense? or ?paper chemistry.? He was so contemptuous of some hypotheses that, when I asked his opinion of them, he merely shook his head, sighed deeply and snickered?as if overcome by the folly of humanity. Stuart Kauffman?s theory of ?autocatalysis? fell into this category. ?Running equations through a computer does not constitute an experiment,? Miller sniffed.

Miller acknowledged that scientists may never know precisely where and when life emerged. ?We?re trying to discuss an historical event, which is very different from the usual kind of science, and so criteria and methods are very different,? he remarked. But when I suggested that Miller sounded pessimistic about the prospects for discovering life?s secret, he looked appalled. Pessimistic? Certainly not! He was optimistic!

One day, he vowed, scientists would discover the self-replicating molecule that triggered the great saga of evolution. Just as the discovery of the microwave radiation pervading space legitimized cosmology, so would the discovery of the first genetic material legitimize Miller?s field. ?It would take off like a rocket,? Miller muttered through clenched teeth. Will such a discovery be immediately self-apparent? Miller nodded. ?It will be in the nature of something that will make you say, ?Jesus, there it is. How could you have overlooked this for so long?? And everybody will be totally convinced.?

When Miller performed his landmark experiment in 1953, most scientists still shared Darwin?s belief that proteins were the likeliest candidates for self-reproducing molecules, since proteins were thought to be capable of reproducing and organizing themselves into cells. After the discovery that DNA is the basis for genetic transmission, many researchers began to favor nucleic acids over proteins as the ur-molecules. But there was a major hitch in this scenario. DNA can make neither proteins nor copies of itself without the help of catalytic proteins called enzymes. This fact turned the origin of life into a classic chicken-or-egg problem: Which came first, proteins or DNA?

In the 1960s the molecular biologist Gunther Stent proposed that this conundrum could be solved by a self-replicating molecule that could act as its own catalyst. In the early 1980?s, researchers identified just such a molecule: ribonucleic acid, or RNA, a single-strand molecule that serves as DNA?s helpmate in manufacturing proteins. Experiments revealed that certain types of RNA could act as their own enzymes, snipping themselves in two and splicing themselves back together again. If RNA could act as an enzyme then it might also be able to replicate itself without help from proteins. RNA could serve as both gene and catalyst, egg and chicken.

But the so-called ?RNA-world? hypothesis suffers from several problems. RNA and its components are difficult to synthesize under the best of circumstances, in a laboratory, let alone under plausible prebiotic conditions. Once RNA is synthesized, it can make new copies of itself only with a great deal of chemical coaxing from the scientist. The origin of life ?has to happen under easy conditions, not ones that are very special,? Miller said. He is convinced that some simpler?and possibly quite dissimilar?molecule must have paved the way for RNA.

Lynn Margulis, for one, doubts whether investigations of the origin of life will yield the kind of simple, self-validating answer that Miller dreams of. ?I think that may be true of the cause of cancer but not of the origin of life,? Margulis said when I spoke to her in 1994. Life, she pointed out, emerged under complex environmental conditions. ?You have day and night, winter and summer, changes in temperature, changes in dryness. These things are historical accumulations. Chemical systems are effectively historical accumulations. So I don?t think there is ever going to be a packaged recipe for life: add water and mix and get life. It?s not a single step process. It?s a cumulative process that involves a lot of changes.?

The smallest bacterium, she noted, ?is so much more like people than Stanley Miller?s mixtures of chemicals, because it already has these system properties. So to go from a bacterium to people is less of a step than to go from a mixture of amino acids to that bacterium.?

Francis Crick once wrote that ?the origin of life appears to be almost a miracle, so many are the conditions which would have to be satisfied to get it going.? (Crick, it should be noted, is an agnostic leaning toward atheism.) Crick proposed that aliens visiting the earth in a spacecraft billions of years ago may have deliberately seeded it with microbes.

Perhaps Stanley Miller?s hope will one day be fulfilled: scientists will find some clever chemical or combination of chemicals that can reproduce, mutate and evolve under plausible prebiotic conditions. The discovery is sure to launch a new era of applied chemistry. (The vast majority of researchers focus on this goal, rather than the elucidation of life?s origin.) But given our lack of knowledge about the conditions under which life began, any theory of life?s origin based on such a finding will always be subject to doubts. Miller has faith that biologists will know the answer to the riddle of life?s origin when they see it. But his belief rests on the premise that the answer will be plausible, if only retrospectively. Who said the origin of life on earth was plausible? Life might have emerged from a freakish convergence of improbable and even unimaginable events.

Moreover, the discovery of a plausible ur-molecule, when or if it happens, is unlikely to tell us what we really want to know: Was life on earth inevitable or a freak occurrence? Has it happened elsewhere or only in this lonely, lonely spot? These questions can only be resolved if we discover life beyond the earth. Society seems increasingly reluctant to underwrite such investigations. In 1993, Congress shut down NASA?s SETI (Search for Extraterrestrial Intelligence) program, which scanned the heavens for radio signals generated by other civilizations. The dream of missions to Mars?manned or otherwise?is growing fainter.

Even so, scientists may find evidence of life beyond the earth tomorrow. Such a discovery would transform all of science and philosophy and human thought. Stephen Jay Gould and Richard Dawkins might be able to settle their argument over whether natural selection is a cosmic or merely terrestrial phenomenon (although each would doubtless find ample evidence for his point of view). Stuart Kauffman might be able to determine whether the ?laws? he discerns in his computer simulations prevail in the real world. If the extraterrestrials are intelligent enough to have developed their own science, physicist Edward Witten may learn whether superstring theory really is the inevitable culmination of any search for the fundamental rules governing reality. Science fiction will become fact. The New York Times will resemble one of those supermarket tabloids that prints ?photographs? of Presidents hobnobbing with aliens. One can always hope.

Postscript: Of?the scientists mentioned above, only Stuart Kauffman, Richard Dawkins and Ed Witten are still alive. Stanley Miller, Lynn Margulis, Gunther Stent,?Stephen Jay Gould and Francis Crick have died, and their scientific survivors seem as far as ever from understanding life?s beginning(s?).

Photo of Stanley Miller from Wikimedia Commons.

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