One of the foremost experiments of the 20th century: Stanley Miller and the origin of prebiotic chemistry

Abstract

Stanley Miller is best known for his classic 1953 experiment on the synthesis of early Earth organic compounds, in the context of the origins of life. However, he did several other experiments that are lesser known and, in some cases, have never been published. The finding in 2007 that Miller had archived dried solutions from his 1950s experiments offered the opportunity of analyzing the products of his early experiments using modern day state-of-the-art techniques. These results, along with Miller’s results, have provided an inventory of the large variety of compounds that include amino acids, amines, simple peptides, hydroxy acids, simple hydrocarbons and urea, which can be synthesized under simulated early Earth conditions.

Full text

MÈTODE 183
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MÈTODE Science Studies Journal, 6 (201 6): 183-189. University of Valencia.
DOI: 10.7203/metode.6.4994
ISS N: 2174 -3487.
Article received: 18/03/2015, accepted: 22/07/2015.
ONE OF THE FOREMOST EXPERIMENTS OF
THE TWENTIETH CENTURY
STANLEY MILLER AND THE ORIGIN OF PREBIOTIC CHEMISTRY
Jeffrey L. BAdA
Stanley Miller is best known for his classic 1953 experiment on the synthesis of early Earth organic
compounds, in the context of the origins of life. However, he did several other experiments that
are lesser known and, in some cases, have never been published. The finding in 2007 that Miller had
archived dried solutions from his 1950s experiments offered the opportunity of analyzing the products
of his early experiments using modern day state-of-the-art techniques. These results, along with
Miller’s results, have provided an inventory of the large variety of compounds that include amino acids,
amines, simple peptides, hydroxy acids, simple hydrocarbons and urea, which can be synthesized under
simulated early Earth conditions.
Keywords: amino acids, spark discharge, reducing atmosphere.
In the fall of 1952, a sixty-year-old Professor and
Nobel Laureate, Harold C. Urey, and a 22-year-old
graduate student, Stanley L. Miller, sat in an ofce
in the Chemistry Department at the University of
Chicago discussing how they might simulate the
conditions and reactions that produced organic
compounds on the early Earth. Miller had heard a
lecture by Urey in the fall of 1951 which stimulated
his interest in a scientic
question long considered to be
intractable: how did life on Earth
originate from inanimate matter.
After waiting almost a year,
Miller nally got the courage
to approach Urey about the
possibility of doing an experiment
to test Urey’s ideas about how
organic compounds might have
been made on the young Earth.
After some hesitation, Urey
agreed to let Miller try to carry
out an experiment, provided he
could produce results within six
months that suggested that the
experiment was worth continuing. The problem that
was the focus of their attention at the 1952 meeting
was how to conduct an experiment that might show
how some of the essential organic compounds thought
to have been important for the origin of life might
have been produced (Bada & Lazcano, 2012).
n MODELING THE EARLY EARTH IN THE
LABORATORY
Urey and Miller recognized that the overall chemical
processes that take place on the surface of the Earth
involved three general components:
energy, the atmosphere, and
the oceans. But how would you
simulate the interaction of these
components in a laboratory-based
experiment? Several types of
energy were thought to be available,
including cosmic and ultraviolet
radiation, radioactive decay, heat
and electrical discharges. They
realized one problem with the use
of radiation and heat as energy
sources was that they were too
energetic and would likely tend to
destroy any organic compounds as
rapidly as they were synthesized.
Thus, they chose to focus on electrical discharges as a
source of energy in their experiment.
Chemists had been experimenting with electric
sparks in gas mixtures since the pioneering eighteenth
«UREY AND MILLER
RECOGNIZED THAT THE
OVERALL CHEMICAL
PROCESSES THAT TAKE
PLACE ON THE SURFACE OF
THE EARTH INVOLVED THREE
GENERAL COMPONENTS:
ENERGY, THE ATMOSPHERE,
AND THE OCEANS»
Rebeca Plana. a.e.i., 2014. Mixed technique on linen, 140 × 180 cm.

184 MÈTODE
On the origin of life
MONOGRAPH
century work by Lord Cavendish, who showed that
the action of a spark discharge in air resulted in the
production of nitrous acid (Cavendish, 1788). During
the nineteenth century there was extensive research
on the synthesis of simple organic compounds
using a variety of conditions. In 1913 Walther Löb
achieved the synthesis of the simple amino acid,
glycine, by exposing wet formamide to a silent
electrical discharge and to ultraviolet light (Löb,
1913). However, it appears that no one had thought
about how these experiments might relate to prebiotic
(before biology) synthesis and the origin of life.
Electric discharges were probably common on
early Earth. The atmosphere must have been subject
to extensive lightning along with corona discharges.
Lightning would also have been associated with
volcanic eruptions that were also likely to have been
common on primitive Earth. In the laboratory, using
a simple commercial Tesla coil, these electrical
discharges can easily be made in order to simulate
these processes.
On the modern Earth, one of the main features
of the atmospheric-ocean interaction, besides
heat exchange, is the evaporation of water and the
condensation of this water from the atmosphere in
the form of precipitation. On the Earth today the
precipitation that falls on the continent is returned to
the oceans by river discharges. On a global average,
rivers discharge about 4.2 × 1016 liters per year of water
into the oceans (Fekete, Vörörsmarty, & Grabs, 2002).
Because the Earth’s oceans contain 1.3 × 1021 liters of
water, this means river water discharge would provide
all the ocean water in only ~30,000 years.
On the early Earth, there were probably a few
major continents, with the only land areas exposed
above the ocean surface being relatively small islands.
Stanley L. Miller at the Botanical Garden of the University of Valencia, during the first Pelegrí Casanova Conference of Biodiversity and
Evolutionary Biology (2003), in front of an exact copy of the glass apparatus he designed in 1953.
Miguel Lo renzo

MÈTODE 185
On the origin of life
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Thus riverine-type water run-off would not have
been a major component of the water cycle. Rather,
precipitation falling directly on the surface ocean
would have been the dominant way water evaporated
from the ocean would be returned to the ocean.
In order to model these overall processes, Urey
and Miller came up with a design for a glass
apparatus that included a water ask connected
to a larger ask connected to
electrodes that provided energy
through electrical discharge
(see Figure 1). The water ask
could be heated to replicate
evaporation. There was also
another connector between the
2 asks that had a condenser
that would act to condense water
from the gas phase and return
it to the water ask, simulating
precipitation. The apparatus
was rst evacuated to remove
any traces of air (oxygen could
have produced an explosion) and
then a gas mixture was added
to it. Urey had proposed that the early atmosphere
was made up of reducing gases such as hydrogen,
methane, and ammonia. Thus when the rst
experiments were carried out the gas mixture used
consisted of these gases.
n THE BIRTH OF PREBIOTIC CHEMISTRY
The rst results were spectacular! Soon after the
spark discharge between the electrodes was started
using the Tesla coil, the glass surfaces and the water
in the apparatus turned brown (Figure 1). By the
end of 6 days, everything was coated with a dark,
gooey material resembling oil. Obviously some sort
of chemistry took had taken place. Miller quickly
stopped the experiment to determine what gases
remained in the ask. Besides the initial gases
hydrogen, methane, and ammonia, after sparking,
carbon monoxide and nitrogen gases were also
present. Based on the nal amounts of methane and
carbon monoxide and the initial amounts of methane,
Miller estimated that 50-60 % of the carbon originally
present as methane had been converted into organic
compounds, the vast majority of which consisted of
complex polymeric materials (Miller, 1955).
Miller next analyzed the water solution and
carried out some simple tests for some specic
organic compounds. He detected amino acids such
as glycine, alanine, b-alanine, and a-amino butyric
acid as well as formic acid, glycolic acid, lactic acid,
acetic acid, and propionic acid. The experiment thus
was the rst to demonstrate how organic compounds
associated with biochemistry could be synthesized
under possible primordial-Earth conditions. The rst
paper was published in Science on 15 May 19531
(Miller, 1953). This was widely covered in the media
and as a result Miller became famous worldwide. He
had just turned 23 years old.
An interesting note about this
renowned publication is that
Miller was the sole author. Urey
had told Miller when the paper
was submitted for publication
that he wanted Miller to be the
only author. Urey felt that, if
he were a co-author, everyone
would give him all the credit.
Miller next set out to further
characterize the various
compounds produced in the
experiment. He tried other
variations of the original
apparatus design as well as
differing the relative amounts of the gases added
to the apparatus. In total, Miller would report that
over 20 different compounds were synthesized in
the experiment. Miller also realized that the pathway
by which the amino acids synthesized was likely the
century-old (at the time of the experiments) Strecker
reaction (Strecker, 1850) in which reactants such as
hydrogen cyanide (HCN), aldehydes, and ketones,
were produced in the spark discharge, and that when
dissolved in the water in the presence of ammonia
they reacted to yield amino acids (after a couple of
1 Miller died on 20 May 2007, 54 years after the publication of this classic
paper. The latest citation index shows this paper has been cited over 2,300
times.
«ANALYSES OF THE VIALS
FROM THE ORIGINAL
EXPERIMENT REPORTED IN
‘SCIENCE’ IN 1953 REVEALED
THAT THIRTEEN AMINO ACIDS
AND FIVE AMINES HAD BEEN
SYNTHESIZED COMPARED
TO THE SEVEN AMINO ACIDS
MILLER HAD REPORTED»
J. L. Bad a
Day: 0 Day: 2 Day: 6
Elèctrodes
Atmosphere
Condenser
Ocean
Figure 1. A time series of the Miller experiment showing the
accumulation of brownish tar. Amino acids and other organic
compounds accumulate in the «Ocean» flask. Frames taken from
a video made in Miller’s laboratory by several of his students and
J. L. Bada circa 1997 and 1998.

On the origin of life
MONOGRAPH
186 MÈTODE
intermediate steps). The same process synthesized the
hydroxy acid Miller detected. The reaction sequences
were as follows:
HCN + Aldehydes/Ketones + NH3 → amino acids
HCN + Aldehydes/Ketones → hydroxy acids
To test whether this reaction sequence explained
some of the compounds Miller detected, he carried out
further analyses on the water solution (Miller, 1957).
He found that after running the experiment for 25
hours, HCN was present at a concentration of ~40 µM
and aldehydes at 1 µM and the total concentration of
amino acids had reached ~2 µM. These components
were not detectable at the start of the experiment.
In addition, the concentration of ammonia steadily
decreased over the course of the experiment. This
provided conclusive proof that the Strecker reaction
was indeed the pathway by which amino acids were
formed in the experiment. Other compounds Miller
detected such as urea could be synthesized simply
from ammonium and cyanate (formed in the spark
discharge), a reaction rst discovered by Friedrich
Wöhler in 1828 (Wöhler, 1828).
n FINDING A HISTORIC TREASURE
Starting in late 1999, Miller suffered a series of
strokes that left him increasingly disabled. In 2005, I
was asked to help clean out his laboratory and ofce
in the University of California, San Diego (UCSD)
Chemistry Department. A large amount of equipment,
chemicals and les were moved into my laboratory and
ofces at the Scripps Institution
of Oceanography (SIO). Then in
March 2007 during a conversation
with Antonio Lazcano, a
mutual friend of Miller’s, it was
mentioned that Miller had once
shown Antonio a box in his ofce
that he said contained portions
of his 1950s experiments. I
immediately realized that this
was likely somewhere among all
of Miller’s material that I had
moved to my laboratories. It took
only a short time to nd two
cardboard boxes with «Electric Discharge» written
on one side that I recognized as Miller’s handwriting.
Inside the boxes were a series of clearly labeled small
boxes containing small, tightly capped glass vials
also labeled (Figure 2). The writing on the labels of
the vials indicated the experiment number and the
pages in his laboratory notebooks where the details
of the experiments are described
(these notebooks are in part of the
Mandeville Special Collections at
the Geisel Library, UCSD).
The vials in the various small
boxes were from experiments
Miller carried out as part of his
thesis research in 1952-54 at the
University of Chicago. Included
were vials from his classic
experiment described in the 1953
Science paper as well as others
from experiments conducted with
two different apparatus designs (Bada & Lazcano,
2003). One differently congured apparatus had an
aspirating nozzle attached to the water-containing ask,
injecting a jet of steam and gas into the spark ask.
A third apparatus design incorporated the aspirator
device, but used a silent discharge instead of electrodes,
an energy source that had been used by others in the
Figure 2. Examples of the boxes of samples containing vials with
portions Miller saved from his early experiments.
«AN INTERESTING ASPECT
OF THE H2S EXPERIMENT WAS
THAT THE OVERALL RELATIVE
AMINO ACID ABUNDANCES
WERE REMARKABLY SIMILAR
TO THOSE FOUND IN
CERTAIN CARBONACEOUS
METEORITES»
Scripps I nstitution of O ceanography, UCSD

MÈTODE 187
On the origin of life
MONOGRAPH
early twentieth century to study
how organic compounds might
have been synthesized in plants
(Bada & Lazcano, 2002). Of
these, the one with the aspirator
device was intriguing because
we surmised it could mimic
a water rich volcanic eruption
accompanied by lightning: thus
it was dubbed the «volcanic»
apparatus.
These archived samples
provided a unique opportunity
to investigate samples prepared
by the pioneer in prebiotic synthesis using state of
the art analytical methods unimaginable to Miller.
We thus proceeded to analyze the vials associated
with his 1952-54 experiments2 (for a more complete
discussion of the results obtained from all the archived
samples analyzed to date, see Bada, 2013). The
residues in the various vials were resuspended in 1
ml aliquots of doubly-distilled water and reacted with
2 Because Miller had found (1957) that the third appa ratus produced lower
yields and a less diverse mixture of amino acids we decided not to analyze
the vials from this experiment.
OPA-NAC (o-phthaldialdehyde/N-acetyl-L-cysteine)
to form highly uorescent amino acid derivatives,
which we characterized by a combination of high
performance liquid chromatography with uorescence
detection, and liquid chromatography-uorescence
detection-time of ight mass spectrometry. Analyses
of the vials from the original experiment reported in
Science in 1953 revealed that thirteen amino acids
and ve amines had been synthesized compared to
the seven amino acids Miller had reported (Table 1).
In addition, analyses of the vials from the «volcanic»
apparatus showed that twenty-one amino acids had
been synthesized along with ve amines (Johnson
et al., 2008). The overall abundances of the various
amino acids and amines appeared to be greater in
comparison to what Miller reported. Hydroxylated
compounds seemed to be preferentially synthesized
in the «volcanic» experiment. This suggests that the
steam injected into the spark apparently splits water
into H• and OH• radicals. The OH• radicals likely
hydroxylated the aldehydes and ketones and these in
turn reacted via the Strecker reaction to produce the
hydroxylated amino acids detected in the extracts.
Publication of these results has rekindled interest in
Miller’s pioneering work.
We next turned our attention to
boxes of vials from experiments
carried out in 1958. For reasons
that are unknown, as far as we
could ascertain, Miller had
never analyzed these after the
experiment was carried out.
One set of vials was from an
experiment in which hydrogen
sulde (H2S) was part of the gas
mixture.
We carried out detailed
analyses of these samples using
the technique described for the
«volcanic» apparatus. In total,
23 amino acids and 4 amines,
including 6 sulfur-containing amino acids and 1 sulfur-
containing amine, were detected (Parker et al., 2011).
There was also evidence indicating that several other
higher carbon amino acids were generated, but at
much lower relative amounts. The H2S experiment also
generated amino acids such as threonine, leucine, and
isoleucine, which were not detected in Miller’s other
spark discharge experiments. In addition, the 1958
H2S experiment provided the rst demonstration of the
production of a variety of organosulfur compounds
from a spark discharge experiment designed to mimic
possible primitive Earth conditions.
Amino acid Moles relative to glycine = 1
Glycine 1.0
Glycolic acid 0.89
Sarcosine (N-methylglycine) 0.08
Alanine 0.54
Lactic acid 0.49
N-Methylalanine 0.02
a-Amino-n-butyric acid 0.08
a-Aminoisobutyric acid 0.002*
a-Hydroxybutyric acid 0.08
b-Alanine 0.24
Succinic acid 0.06
Aspartic acid 0.006
Glutamic acid 0.01
Iminodiacetic acid 0.09
Iminoacetic-propionic acid 0.02
Formic acid 3.70
Acetic acid 0.24
Propionic acid 0.21
Urea 0.03*
* Likely low be cause Miller did n ot realize the ninhyd rin detection m ethod he used ha d a lower
respons e for this amino aci d compared with th e other amino aci ds.
Table 1. Yields in moles (relative to glycine = 1) of the various
compounds Miller detected in his spark discharge experiments. The
amount of carbon added in the form of methane was 710 mg. The
amount of glycine synthesized was 4.8 mg.
Source: B ased on Miller a nd Urey, 1959.
«HOW MILLER GOT THE
IDEA OF USING CYANAMIDE
IN A SPARK DISCHARGE
EXPERIMENT, NEARLY A
DECADE BEFORE THIS
WAS SUGGESTED BY
OTHERS AS AN AGENT FOR
POLYMERIZING AMINO ACIDS,
IS A MYSTERY»

On the origin of life
MONOGRAPH
188 MÈTODE
An interesting aspect of the H2S experiment was
that the overall relative amino acid abundances
were remarkably similar to those found in certain
carbonaceous meteorites (Parker et al., 2011). Various
lines of evidence suggest that the meteorite amino acids
were synthesized during an early aqueous alteration
process on the asteroid that was the parent body of the
meteorite (Bada, 2013; Burton, Stern, Elsila, Glavin,
& Dworkin, 2012; Peltzer, Bada, Schlesinger, &
Miller, 1984). It is likely that reactants such as HCN,
aldehydes/ketones and ammonia had been synthesized
elsewhere in which, besides gases such as methane and
hydrogen, H2S was a component. These reactants were
then incorporated into the parent bodies where amino
acids were eventually synthesized by water liberated in
the interior that percolated to the surface.
Several additional boxes of samples still remained in
the collection we had found. After carefully reviewing
these for differences in gas mixture composition,
apparatus design, etc., we decided to next direct our
attention to another set of 1958 samples in which
Miller had carried out an experiment that involved
sparking a gas mixture of CH4, NH3, and H2O, while
intermittently adding the plausible prebiotic condensing
agent cyanamide during the course of the experiment.
Nearly fty years ago, cyanamide was found to be
synthesized from reduced gases by UV light and was
proposed to be a possible prebiotic condensing agent
(Schimpl, Lemmon, & Calvin, 1965). How Miller
got the idea of using cyanamide in a spark discharge
experiment, nearly a decade before this was suggested
by others as an agent for polymerizing amino acids, is
a mystery.
Our analyses found that more than 12 amino acids,
10 glycine-containing dipeptides, and 3 glycine-
containing diketopiperazines (DKPs), cyclic dipeptides,
were synthesized in the experiment (Parker et al., 2014).
However, there was a problem: previous studies of the
polymerization of amino acids by cyanamide indicated
that the reaction took place at acidic pH values whereas
the pH of the spark discharge solute was 8.5-9 (this
was because of the ammonia in the spark discharge
experiment). We conrmed this using an aqueous
amino acid solution also containing cyanamide heated
at pH values ranging from 2-3 to 10. Our results
conrmed that the polymerization was optimal at
acidic pH. We suspected that the intermediates in the
Strecker reaction leading to amino acids, amino acid
nitriles, and amides, might be reacting with cyanamide
rather than the amino acids themselves. We tested
this using aqueous solutions at various pH values that
contained either the amino acid nitrile or amino acid
amide along with cyanamide. The results showed
«MILLER’S PIONEERING STUDIES HELPED
DEFINE THE PROCESSES THAT PROVIDED
THE PREBIOTIC CHEMICAL INVENTORY
NEEDED FOR CHEMICAL EVOLUTION AND
EVENTUALLY THE ORIGIN OF LIFE»
Amino Acids Amines Peptides
Glycine Methylamine Glycyl-alanine
Alanine Ethylamine Glycyl-threonine
β-Alanine Ethanolamine Glycyl-proline
Serine Isopropylamine Prolyl-glycine
Isoserine N-Propylamine Glycyl-valine
a-Aminoisobutyric acid Cysteamine Valyl-glycine
β-Aminoisobutyric acid Glycyl-glutamic acid
a-Aminobutyric acid Glutamyl-glycine
β-Aminobutyric acid Leucyl-glycine
g-Aminobutyric acid cyclo(Glycyl-glycine)
Homoserine cyclo(Glycyl-Proline)
a-Methylserine cyclo(Leucyl-Glycine)
Threonine
Aspartic acid
β-Hydroxyaspartic acid
Valine
Isovaline
Norvaline
Ornithine
Glutamic acid
a-Methylglutamic acid
Leucine
Isoleucine
a-Aminoadipic acid
Phenylalanine
Homocysteic acid
S-Methylcysteine
Methionine
Methionine sulfoxide
Methionine sulfone
Ethionine
Table 2. The various amino acids, amines and peptides detected in
the 1950s Miller spark discharge experiments.
Source: J ohnson et al., 2 008; Parker et al ., 2011; Parker et a l., 2014.

MÈTODE 189
On the origin of life
MONOGRAPH
that polymerization at pH 8.5-10 did, indeed, yield
dipeptides with the main reactive species being the
amino acid amide. These experiments conrmed that
intermediates in the Strecker synthesis of amino acids
play a key role in facilitating polymerization in the
presence of cyanamide.
Miller’s cyanamide experiment highlights the
potential importance of condensing agents in
providing a mechanism to explain how simple
organic compounds like amino acids may have
polymerized to form more complex biomolecules,
such as dipeptides. The synthesis of dipeptides and
diketopiperazines by the cyanamide polymerization
reaction may have additional implications, as some
dipeptides and DKPs have been found to have
catalytic properties that may have been important on
the primordial Earth (Weber & Pizzarello, 2006).
n CONCLUSIONS
Miller’s pioneering studies helped dene the
processes that provided the prebiotic chemical
inventory needed for chemical evolution and
eventually the origin of life. The re-analyses using
modern state-of-the-art analytical methods of
archived portions that Miller had saved from his
ground-breaking experiments in 1950s have found
that he synthesized 31 amino acids, 6 amines, and
12 dipeptides/cyclodipeptides (Table 2). Miller’s
studies of the use of a prebiotic condensation agent
suggests there are plausible pathways for generating
more complex molecules from simple ones such as
amino acids. Although much still needs to be done,
the realization that the continuous prebiotic chemical
evolution can likely generate molecules that have
increasing complexity is important. As this increase
in chemical complexity continued, polymers with
some sort of primitive catalytic functions, were
eventually produced. This, in turn, evolved into a
complex polymeric molecule that could catalyze its
own imperfect replication. It marked the point of both
the origin of life and evolution.
In the book Elegant solutions: Ten beautiful
experiments in chemistry (Ball, 2005), Miller’s
seminal work is selected along with such notable
achievements by Henry Cavendish, Louis Pasteur,
Ernest Rutherford, and Marie and Pierre Curie. This
is certainly a tting recognition of Miller’s classic
research.
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Jeffrey L. Bada. Distinguished Research Professor, and Distinguished
Professor Emeritus, of Marine Chemistry at the Scripps Institution of
Oceanography, University of California, San Diego (USA). He obtained
his PhD in Chemistry at UCSD in 1968 where Stanley Miller supervised
his thesis research. His research deals with the environments on the early
Earth that provided the optimal conditions for the synthesis of organic
compounds required for the origin of life.