Origin of Life

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Feature Articles
The Origin of Life

A case is made for the descent of electrons
James Trefil, Harold J. Morowitz and Eric Smith
A s the frontiers of knowledge have

advanced, scientists have resolved
one creation question after another. We
and no answer to the old problem of
which came first.
In this article we present a view gain-
(lightning), without the mediation of
enzymes. This finding triggered a wave
of new thinking about both the origin
now have a pretty good understanding ing attention in the origin-of-life com- and nature of life. (Today, the consensus
of the origin of the Sun and the Earth, munity that takes the question out of is that Miller and Urey had the wrong
and cosmologists can take us to within the hatchery and places it squarely in atmospheric components in their ap-
a fraction of a second of the beginning the realm of accessible, plausible chem- paratus, so the process they discovered
of the universe itself. We know how life, istry. As we see it, the early steps on the was probably not representative of the
once it began, was able to proliferate way to life are an inevitable, incremen- emergence of life on Earth. It neverthe-
and diversify until it filled (and in many tal result of the operation of the laws of less pointed to the potential fecundity
cases created) every niche on the planet. chemistry and physics operating under and diversity of nonenzymatic primor-
Yet one of the most obvious big ques- the conditions that existed on the early dial chemistry.)
tions—how did life arise from inorganic Earth, a result that can be understood Since 1953, we have found many of
matter?—remains a great unknown. in terms of known (or at least know- the same simple organic molecules in
Our progress on this question has able) laws of nature. As such, the early meteorites, comets and even interstellar
been impeded by a formidable cogni- stages in the emergence of life are no gas clouds. Far from being special, then,
tive barrier. Because we perceive a deep more surprising, no more accidental, the simplest of the molecules we find in
gap when we think about the differ- than water flowing downhill. living systems—life’s building blocks—
ence between inorganic matter and life, The new approach requires that we seem to be quite common in nature. To
we feel that nature must have made a adopt new ways of looking at two im- many, the real question was how these
big leap to cross that gap. This point portant fields of science. As we will basic building blocks got put together
of view has led to searches for ways see below, we will have to adjust our into living systems, and, equally impor-
large and complex molecules could view of both cellular biochemistry and tant, how the molecules that led to mod-
have formed early in Earth’s history, a thermodynamics. Before we talk about ern life were selected out of the messy
daunting task. The essential problem is these new ideas, however, it will be use- molecular milieu in which they arose.
that in modern living systems, chemical ful to place them in context by outlining The ubiquity of simple molecules
reactions in cells are mediated by pro- a little of the history of research on the suggested an appealing scenario that
tein catalysts called enzymes. The in- origin of life. had a profound effect on the way in-
formation encoded in the nucleic acids vestigators approached the origin of
DNA and RNA is required to make the The Origin of Origins life throughout the last half of the 20th
proteins; yet the proteins are required Most historians would say that the mod- century. The scenario went like this: Af-
to make the nucleic acids. Furthermore, ern era of experimental research in ori- ter the Earth cooled enough to allow
both proteins and nucleic acids are large gin-of-life studies began in a basement oceans to form, the Miller-Urey process
molecules consisting of strings of small laboratory in the chemistry department or something like it produced a rain
component molecules whose synthesis of the University of Chicago in 1953. of organic matter. In a relatively short
is supervised by proteins and nucleic Harold Urey, a Nobel laureate in chem- time, the ocean became a broth of these
acids. We have two chickens, two eggs, istry, and Stanley Miller, then a graduate molecules, and given enough time, the
student, put together a tabletop appa- right combination of molecules came
ratus designed to look at the kinds of together by pure chance to form a repli-
James Trefil is Clarence J. Robinson Professor of chemical processes that might have oc- cating entity of some kind that evolved
Physics at George Mason University. Harold
curred on the planet soon after its birth. into modern life.
Morowitz is Clarence J. Robinson Professor of
Biology and Natural Philosophy at George Mason
They showed that organic molecules (in Scientists called this scenario the
University. Eric Smith is a professor at the Santa this case amino acids) could be created Oparin-Haldane conjecture, but it was
Fe Institute. Address for Trefil: 207F East Building, from inorganic materials by natural en- given a provocative nickname that en-
MS 1D6, George Mason University, Fairfax, VA vironmental conditions such as acidic dures in the popular consciousness—
22030. Internet: jtrefil@gmu.edu. solution, heat and electrical discharge Primordial Soup.
© 2009 Sigma Xi, The Scientific Research Society. Reproduction

206 American Scientist, Volume 97
with permission only. Contact perms@amsci.org.
Figure 1. Origin-of-life studies became an experimental science with the Miller-Urey experiment, which produced organic molecules in a flask
from components thought to be present in the paleogeological atmosphere—homemade primordial soup. But how did soup ingredients become
life? A recent model called Metabolism First proposes that life didn’t climb over a thermodynamic barrier, it fell into place according to know-
able laws of chemistry and thermodynamics. (Image courtesy of Scripps Institution of Oceanography, University of California, San Diego.)
The essential legacy of the Primor- catalysts. The frozen-accident argu- the relevance of their findings to the
dial Soup was twofold: It simplified the ment was then replaced by a sugges- origin of life depends.
notion of the origin of life to a single tive scenario in which something like Inserting RNA molecules into an
pivotal event, and then it proposed that RNA was assembled by chance, and RNA First scenario without explaining
that event—the step that occurred after was then able to fill twin roles as both how they got there seems to us an inad-
the molecules were made—was a result enzyme and hereditary molecule in equate foundation for an origin theory.
of chance. In the standard language, life the runup to life. The RNA systems The RNA molecule is too complex, re-
is to be seen, in the end, as a “frozen ac- were then acted upon by natural se- quiring assembly first of the monomeric
cident.” In this view, many fundamen- lection, leading to greater molecular constituents of RNA, then assembly of
tal details about the structure of life are complexity and, eventually, something strings of monomers into polymers. As
not amenable to explanation. The archi- like modern life. Whereas most scien- a random event without a highly struc-
tecture of life is just one of those things. tists believe, on the basis of Cech and tured chemical context, this sequence
Although many modern theories are Altman’s work, that life went through has a forbiddingly low probability and
less extreme than this, frozen-accident an early RNA-dominated phase the process lacks a plausible chemical
thinking still influences what some of (dubbed “RNA World”), the “RNA explanation, despite considerable effort
us ask about the origin of life and how First” scenario has again a quality of to supply one. We find it more natural
we prioritize our experiments. frozen accident. Between prebiologi- to infer that by the time complex RNA
cal chemistry and RNA World, a large was possible, life was already well
RNA World leap occurs, requiring that molecules on the road to complexity. We believe
The next major advance came in the appear having at least a familial re- further that we can see the primordial
early 1980s, when Thomas Cech and semblance to the complex molecules chemical architecture preserved in the
Sidney Altman showed that some in the vials of Cech and Altman, for universal metabolic chemistry we ob-
RNA molecules can act as enzyme-like that is the assumption upon which serve today.

www.americanscientist.org 2009 May–June 207
(FOFUJDT'JSTU3/"8PSME .FUBCPMJTN'JSTU continuity across generations, as it does
today. Depending on which function
TPVQJOHSFEJFOUT one prefers to emphasize, these overall
TNBMMDBSCPOCBTFENPMFDVMFT models have been called “Control First”
or “Genetics First.” In either case, the
proliferation of metabolism depended
on RNA being there first.
Adherents have come to call the
other possibility “Metabolism First”
/VDMFJDBDJE (though by this they have meant many
NPOPNFSTGPSN slightly different things). In our version
of Metabolism First, the earliest steps
/POFO[ZNBUJD toward life required neither DNA nor
DBUBMZTUT RNA, and may not even have involved
FYQBOE spatial compartments like cells; the ear-
DIFNJDBM liest reactions could have occurred in
JOWFOUPSZ
the voids of porous rock, perhaps filled
with organic gels deposited as suggest-
ed in the Oparin-Haldane model. We
believe this early version of metabolism
consisted of a series of simple chemi-
cal reactions running without the aid
of complex enzymes, via the catalytic
.POPNFST action of networks of small molecules,
DPNCJOF 1PMZNFST
perhaps aided by naturally occurring
DBUBMZ[F
GPSNBUJPOPG minerals. If the network generated its
/FUXPSLTPGSFBDUJPOT
NPOPNFST own constituents—if it was recursive—
BSJTFDZDMJDSFBDUJPO
TFRVFODFTQSPWJEFB
it could serve as the core of a self-ampli-
QBUIXBZUPMPXFS fying chemical system subject to selec-
FOFSHZMFWFMTGPS tion. We propose that such a system
IJHIFOFSHZFMFDUSPOT arose and that much of that early core
QSPEVDFEJOQSJNPSEJBM remains as the universal part of mod-
FOWJSPONFOU ern biochemistry, the reaction sequenc-
1PMZNFSTEJSFDUBTTFNCMZ es shared by all living beings. Further
PGJEFOUJDBMQPMZNFST elaborations would have been added
to it as cells formed and came under
4FMFDUJPOMFBETUPJODSFBTFE RNA control, and as organisms special-
DBUBMZUJDWFSTBUJMJUZNFUBCPMJTN ized as participants in more complex
DPOUJOVFTUPFWPMWFJOUPJUTQSFTFOU ecosystems.
GPSN
Networks of synthetic pathways
that are recursive and self-catalyzing
are widely known in organic chemistry,
but they are notorious for generating
a mass of side products, which may
disrupt the reaction system or simply
dilute the reactants, preventing them
from accumulating within a pathway.
4FMFDUJPOQSPNPUFTFGGJDJFODZBOE The important feature necessary for
BDRVJTJUJPOPGBEEJUJPOBMGVODUJPOT0WFS chemical selection in such a network,
UJNF %/"UBLFTPWFSJOGPSNBUJPOTUPSBHF
which remains to be demonstrated, is
GVODUJPO QSPUFJOTUBLFPWFSDBUBMZUJDBOE
TUSVDUVSBMGVODUJPOT feedback-driven self-pruning of side
reactions, resulting in a limited suite of
pathways capable of concentrating re-
Figure 2. RNA World has been the prevailing theory for the origin of life since the 1980s. The
emergence of a self-replicating catalytic molecule accounts for signature capabilities of living agents as metabolism does. The search
systems, but it doesn’t explain how the protobiological molecule itself arose. Metabolism First for such self-pruning is one of the most
seeks the answer in primitive reaction networks that generate their own constituents, offering actively pursued research fronts in Me-
a substrate for chemical selection and a launchpad for life. tabolism First research.
The compelling feature of RNA World ity of these primordial RNA molecules A Pair of Analogies
is that a primordial molecule provided increased due to random variation and Here’s an analogy that will provide
both catalytic power and the ability to selection, metabolic complexity began an outline for the argument we make:
propagate its chemical identity over to emerge. From that stage, RNA had Consider the requirements of the U.S.
generations. As the catalytic versatil- roles in both control of metabolism and Interstate highway system. The system

includes an enormously complex net- Metabolism 101
work of roads; major infrastructure de-
voted to extracting oil from the Earth, "UBOZHJWFONPNFOUJOBMJWJOHDFMM IVOESFETPGSFBDUJPOT
FO[ZNF
refining oil into gasoline and distrib- PDDVSJOXIJDIDIFNJDBMQSFDVSTPSTBSFDPOWFSUFEJOUP
QSFDVSTPS QSPEVDU
uting gasoline along the highways, a QSPEVDUT/FBSMZBMMPGUIFTFSFBDUJPOTXPVMEOPUPDDVS
XJUIPVUUIFBTTJTUBODFPGFO[ZNFT QSPUFJOTUVOFE
major industry devoted to producing
CZFWPMVUJPOUPCJOESFBDUBOUTXJUIBTUPOJTIJOHTQFDJGJDJUZ PGUFOJOQBJST GBDJMJUBUFUIFSFBDUJPO
automobiles; and so on. If we wanted CFUXFFOUIFNBOESFMFBTFUIFQSPEVDUT
to explain this system in all of its com-
plexity, we would not ask whether cars 5IFSFBDUJPOTDBSSJFEPVUCZFO[ZNFTIBWFBUIFSNPEZOBNJD FOFSHZ
led to roads or roads led to cars, nor GFBUVSFJODPNNPOUIFPWFSBMMFOFSHZPGUIFQSPEVDUTJTMFTT
would we suspect that the entire sys- UIBOUIBUPGUIFSFBDUBOUT
tem had been created from scratch as a 1VUBOPUIFSXBZ UIFGMPXPGNFUBCPMJDSFBDUJPOTJTJOUIFEJSFDUJPOPGFRVJMJCSJVN&O[ZNFT MJLFBMM
giant public works project. It would be DBUBMZTUT EPOPUBGGFDUUIFQPTJUJPOPGFRVJMJCSJVNBUBMM UIFZKVTUIFMQDIFNJDBMTQFDJFTBDIJFWF
more productive to consider the state FRVJMJCSJVNGBTUFSPGUFONJMMJPOTPGUJNFTGBTUFSUIBOUIFZXPVMEXJUIPVUUIFDBUBMZTUQSFTFOU
of transport in preindustrial America
*ODFMMT NFUBCPMJDSFBDUJPOTPDDVSJOTFRVFODFTDBMMFEQBUIXBZT5IFQSPEVDUTPGUIF
and ask how the primitive foot trails
FO[ZNFDBUBMZ[FESFBDUJPOTJOQBUIXBZTBSFBDUFEVQPOCZPUIFSFO[ZNFT
that must certainly have existed had
developed into wagon roads, then
paved roads and so on. By following FOFSHZ
this evolutionary line of argument, we
would eventually account for the pres-
ent system in all its complexity without
needing recourse to highly improbable 3FBDUJPOTGPSXIJDIUIFESPQJOFOFSHZJTIJHIBSFDBMMFEJSSFWFSTJCMF*OUIFDPOEJUJPOTGPVOEJO
chance events. DFMMT UIFZSVOJOUIFGPSXBSEEJSFDUJPOPOMZ'PSNBOZDFMMVMBSSFBDUJPOT MJLFUIFIPSJ[POUBM
In the same way, we argue, the cur- SFBDUJPOTJOUIFGJHVSFBCPWF UIFDIBOHF
rent complexity of life should be un- JOFOFSHZGPSUIFSFBDUJPOJTOFBS[FSP
*GUIFQSPEVDUCFHJOTUPQJMFVQ JOIJCJUPS
derstood as the result of a multistep
QFSIBQTCFDBVTFUIFBDUJWJUZPG FOFSHZ
process, beginning with the catalytic
BOFO[ZNFGVSUIFSEPXOUIF
chemistry of small molecules acting in QBUIXBZJTJOUFSGFSFEXJUICZB
simple networks—networks still pre- DIFNJDBMJOIJCJUPS
UIFSFBDUJPOQBJSXJMM
served in the depths of metabolism— BDIJFWFFRVJMJCSJVNCZSVOOJOHJOUIFSFWFSTFEJSFDUJPOVOUJMUIFSFJTBHBJOBO
elaborating these reaction sequences FRVJMJCSJVNCBMBODFCFUXFFOSFBDUJPOBOEQSPEVDU5IFDIBOHFJOUIFDPODFOUSBUJPOTPG
through processes of simple chemical SFBDUBOUNBZCFBDDPNQBOJFECZJODSFBTFEUSBGGJD iGMVYu
JOUPCSBODIJOHSFBDUJPOT
selection, and only later taking on the
"GUFSGPVSCJMMJPOZFBSTPGFWPMVUJPOBSZUJOLFSJOH UIFDFMMIBTDPOKVSFEUIFTQSBXMJOH XJOEJOH
aspects of cellularization and organis-
TFRVFODFPGSFBDUJPOTGPVOEJONPEFSODFMMT DBQUVSFEJOUIFGBNPVTNFUBCPMJDNBQTUFBEJMZ
mal individuality that make possible SFGJOFECZ%POBME/JDIPMTPOPG-FFET6OJWFSTJUZTJODFBOEGPVOEPOMBCPSBUPSZXBMMT
the Darwinian selection that biologists FWFSZXIFSF
see today. Our task as origin-of-life re- Donald Nicholson
searchers is to look at the modern high- )PXEJEUIJTBTUPVOEJOHTZTUFN
ways and see what they reveal about DPNFJOUPCFJOH #VSJFEJOUIJT
NB[FJTBDJSDVMBSQBUIXBZPG
the original foot trails.
SFBDUJPOT PGUFODBMMFEUIFIVCPG
The very robustness of modern life NFUBCPMJTN UIBUUIFBVUIPST
makes such questions difficult, because CFMJFWFNBZCFUIFGPVOEBUJPOPG
the metabolism that we see today seems MJGFJUTFMGUIFQMBDFXIFSFJUBMM
to be one on which life has converged, TUBSUFE
and around which it reorganizes after
historical shocks such as the oxygen-
ation of the atmosphere at the begin- OX A L OA C E T A T E
ning of the paleoproterozoic era, the
emergence of multicellularity, dramatic C IT R A T E
climate changes that have reshaped en-
vironments and so on. To avoid con- IS OC IT R A T E
fusing this convergent form with one
toward which evolution was “direct- MA L A T E
ed,” we focus instead on the nonliv- 2-OXO -
G L UT A R A T E
ing world that preceded life and ask
“what was wrong” with such a world, F UMA R A T E
which created the first steps toward life S UC C INY L -C oA
as a departure. In other words, what
was the “problem” that a lifeless earth S UC C INA T E $P"
“solved” by the emergence of life?
Another analogy will illustrate how
this question should be understood.

DJUSJDBDJEDZDMFGPSXBSE PYJEBUJWF
EJSFDUJPO QSJNPSEJBMDJUSJDBDJEDZDMFSFWFSTF SFEVDUJWF
EJSFDUJPO
iBDUJWBUFEu $0 )
BDFUBUF HFPMPHJDBMMZ
)0 DBSCPO QSPEVDFEIJHI
FOFSHZFMFDUSPOT
PYZHFO
TVSSFOEFSFOFSHZ
IZESPHFO UPSFEVDUJWFDZDMF
USBOTGFSPGIJHI
FOFSHZFMFDUSPOTUP iBDUJWBUFEuBDFUBUF
FOFSHZIBSWFTUJOH $0XBTUF QSPEVDUFOUFST
QBUIXBZT QSPEVDUT CJPTZOUIFUJDQBUIXBZT
Figure 3. The reactions and molecules of the citric acid cycle are universal in modern organisms. However, in many microbial species, the cycle
runs in reverse. Instead of oxidizing the fuel molecule acetate (“activated” by attachment to a carrier molecule) and releasing CO2 as waste, the
reverse cycle incorporates CO2 in organic molecules by exploiting the electron-transfer potential (“reducing power”) of geologically produced
molecules such as H2. A reductive cycle could have served as the foundation for primordial biosynthesis.
Imagine a large pond of water sitting nel ”solves” this problem by allowing lowered if the electrons in the hydrogen
on top of a hill. We know that there are the water to move to a lower energy ”roll down the hill” by combining with
any number of other states—any in state. Furthermore, the dynamics of the the atoms of carbon dioxide in a chemi-
which the water is lower than it is at system are such that once the channel cal reaction that produces water and
the top—which have lower energy and is established, subsequent flow will
are therefore states toward which the reinforce and strengthen it. There are $0 )
system will tend to evolve over time. many such systems of channels in na-
In terms of our question, the ”problem” ture—the lightning bolt is an example,
faced by the system is how to get water although in that case the forces at work
from its initial state to any state of lower are electrical, not gravitational. (When WFSZTMPX
energy—how to get the water down lightning occurs, positive and negative XJUIPVU
the hill. We need not think of the laws charges become separated between DBUBMZTU
of physics as being endpoint directed; clouds and the ground. The charge sep-
rather, they simply adjudicate between aration ionizes atoms in the air, creating
states of higher or lower energy, with a a conducting channel through which
preference for lower. Can we apply the the charges flow—the lightning bolt— BDFUBUF )0
same reasoning to the chemistry of life? much as water flows down a hill).
For real hills, we understand not only We argue that the appearance of life acetate (a molecule with two carbon at-
that the water will flow downward but on our planet followed the creation of oms). In the abiotic world, however,
also many things about how it will do just such a channel, except that it was a this particular reaction takes place so
so. Molecules of water will not each channel in a chemical rather than a geo- slowly that the electrons in the hydro-
flow down a random path. Instead the logical landscape. In the abiotic world of gen molecles find themselves effectively
flowing water will cut a channel in the the early Earth, likely in a chemically ex- stranded at the top of the energy hill.
hillside. In fact, the flow of water is at cited environment, reservoirs of energy In this example, the problem that
once constructing a channel and con- accumulated. In effect, electrons (along is solved by the presence of life is get-
tributing to the collapse of the energy with certain key ions) were pumped ting energized electrons back down the
imbalance that drives the entire process. up chemical hills. Like the water in chemical hill. This is accomplished by
In addition, if we look at this process in our analogy, those electrons possessed the establishment of a sequence of bio-
detail, we see that what really matters stored energy. The “problem” was how chemical channels, each contributing to
is the configuration of the earth near to release it. In the words of Albert the whole. (Think of the water cutting
the top of the hill, for it is there that the Szent-Gyorgi: “Life is nothing but an multiple channels in the hill). The reac-
channeling process starts. This part of electron looking for a place to rest.” tions that create those channels would
the analogy turns out to be particularly For example, carbon dioxide and hy- involve simple chemical transactions
appropriate when we consider early drogen molecules are produced copi- between small organic molecules.
chemical reactions. ously in ordinary geochemical environ- How can we translate these sorts of
In the analogy, the “problem” is the ments such as deep sea vents, creating a general arguments into a reasonable
fact that the water begins in a state of situation analogous to the water on the scenario for the appearance of the first
high energy; the creation of the chan- hill. The energy of this system can be living thing? One way would be to look

closely at the metabolic chart shown $0 ) captures only part of the energy in the
earlier, the diagram that maps the basic carbon dioxide and hydrogen that con-
chemical reactions in all living systems. stitute its input. In transforming the car-
At the very core of metabolism—the bon dioxide to acetate, for example, the
starting point for the synthetic path- cycle harvests only about a third of the
ways of all biomolecules—is a relatively energy available in the electrons. Even
simple set of reactions known as the cit- in the deep core of metabolism, how-
ric acid cycle (also called the tricarbox- ever, we do not see the cycle in isolation.
ylic acid cycle or the Krebs cycle). The Its lowest-energy molecule, acetate, is
cycle involves eight molecules, each a the starting point for other pathways
SFEVDUJWFDJUSJDBDJEDZDMF
carboxylic acid (a molecule containing that make the essential oils used in cell
—COO groups). In most present-day membranes, harvesting another third
life forms on Earth, the citric acid cycle of the electron energy. Further reactions,
operates to break organic molecules such as those that generate methane,
down into carbon dioxide and water, can capture the remaining available en-
using oxygen to produce energy for the ergy, though methane is a gas and there-
cell—in effect, ”burning” those mol- fore a waste product, unlike the earlier
ecules as fuel. (Technically, a molecule molecules in the pathway, which are
like glucose is first broken down into constituents of biomass.
smaller molecules like pyruvate, which BDFUBUF )0
is then fed into the citric acid cycle. Full Selection Begins
decomposition of pyruvate to CO2 and acting to mediate and speed up the We note that there is a fundamental dif-
water is facilitated by transfer of high- reaction. On biochemical and thermo- ference between the way chemical reac-
energy electrons to certain coreactants dynamic grounds, then, the reductive tion systems could have operated before
that, in the modern cell, ferry the elec- citric acid cycle (or some simpler pre- the appearance of the first self-replicat-
trons to other reactions). When the cycle cursor) would be a good candidate for ing molecules and the way they operate
operates in this way, we say that it is in the threshold of early life—the point now that self-replicating systems have
its oxidative mode. where the pond of high-potential water developed. In the beginning, the only
The cycle can also operate in the op- is breached and the downhill pathway potential source of order would have
posite direction, taking in energy (in is etched out. The slow uncatalyzed been networks of chemical reactions op-
the form of high-energy electrons) and conversion of carbon dioxide and hy- erating according to the laws of chem-
building up larger molecules from drogen into acetate and water, shown istry and physics. After molecules ap-
smaller ones. This is called the reduc- earlier, occurs efficiently as the energy peared that could replicate more or less
tive mode of the cycle. If an organism and reactants enter a primordial net- independently, such as RNA, however,
has access to high-energy electrons like work of reactions like the modern-day evolution could have proceeded ac-
those produced by geochemical pro- reductive citric acid cycle. cording to the rules of natural selection,
cesses, in fact, it can thrive with the In the metabolic maps of all modern with the success of subsequent genera-
cycle exclusively in the reductive mode, organisms, the small molecules and re- tions dependent on adaptive properties.
having no use for the oxidative mode actions of the citric acid cycle are the Exactly when and how this transition
at all. One way to think about the two starting point of every biosynthetic occurred remains an open question de-
modes of the cycle is this: In the oxida- pathway—all roads lead from the citric bated by researchers, but the fact that
tive mode, the input is an organic mole- acid cycle. However, in some organisms it did occur is plain. Another way of
cule, and the output is chemical energy, the reactions do not form a closed—cy- saying this is that before the appearance
carbon dioxide and water. In the reduc- clic—reaction sequence. For that rea- of the first self-replicating molecules or
tive mode, the input is chemical energy, son, even among researchers convinced assemblages of molecules (and, again,
carbon dioxide and water, and the out- that these reactions are vestiges of the we have to emphasize that these may
put is a more complex molecule. first metabolism, debate remains over or may not have been inside cells), what
This must have been the way the cy- whether the very first metabolic foot- mattered was the persistence of the
cle operated on the early Earth, because path was a cycle. However, because chemical network; after such a system
molecular oxygen was not available only cycles can act as self-amplifying appeared, natural selection took on its
primordially to support the oxidative channels, and because in organisms not more familiar form of selection among
mode, and because we see it operating running the closed cycle, sophisticated rival reproducing “individuals.”
this way today in some anaerobic or- compensating adaptations are required, Once natural selection began, sys-
ganisms that seem to have preserved we consider a primordial reductive tems with slightly different chemistry
this aspect of the biochemistry of their citric acid cycle the most likely route would appear on the scene through
ancestors. In the reductive mode, the from geochemistry to life—the rivulet random accident. For example, acetate
cycle provides a way for high-energy that formed at the top of the energy can be used in two ways to make oily
electrons to flow down the chemical hill, through which the pond of energy molecules, and the major domains of
hill. It is similar to the acetate reaction began its thermodynamic escape. We life divide, in part, according to which
shown earlier, which is thermodynami- then ask how, from this simple begin- class they make and how they use them.
cally feasible but very slow, but with ning, could the complexity we see in Methane production purely for energet-
the addition of a network of small mol- the modern cell arise. The first thing to ic purposes may have been primordial,
ecules—the reductive citric acid cycle— notice is that, taken by itself, the cycle or it may have been coupled to metabo-

mordial organisms as a waste prod-
GBUUZBDJET
uct. As they adapted, organisms did
not abandon the reductive citric acid
DBSCPIZESBUFT cycle, which we believe was the unique
foundation for biosynthesis. Instead
they acquired the ability to run the cycle
BDFUBUF
in reverse, extracting energy from the
breakdown of molecules similar to those
the cycle formerly produced.
The role of the citric acid cycle as a
foundation for complexity applies not
only to subsequent adaptation by organ-
SFEVDUJWF isms under selection; it can be seen even
BNJOPBDJET
DJUSJDBDJE within the chemical structure of the met-
OVDMFPUJEFT
DZDMF abolic core itself. A particularly powerful
way to make this point is to rework the
schematic chart of current metabolism
BNJOPBDJET
first developed by Nicholson. The origi-
nal Nicholson chart was developed to
elaborate human metabolism and was
Figure 4. The famous metabolic map on page 209 was recently reworked to feature metabolism
of chemoautotrophs—organisms that derive energy from inorganic sources and synthesize all gradually expanded to incorporate the
necessary compounds from CO2. Arraying the reactions in concentric rings reveals a short complex webs of chemistry on which
route to essential biological products. humans depend. Recently, one of us
(Morowitz) and Vijay Srinivasan used
lism in a later, more complicated age recognized by Darwin as distinctive of evidence from microbiology to distill the
(another topic of serious debate among life. After such an age has begun, it can Nicholson chart, with its complex mod-
researchers investigating the deepest maintain the complexity and diversity ules and domains of metabolism, down
branches of the tree of life). needed to explore for refinements—in to a minimal common core, the neces-
The important pattern to appreciate efficiency, in adaptation to the geologi- sary and sufficient network of reactions
is that the primordial cycle provides cal environment or in specialized divi- to make a living system. Within this core
the stability and starting materials that sion of labor within communal systems. chart, which will be published soon, we
make an age of selection possible. We The same pattern repeated itself when arrayed pathways as layers built around
think it was at the transition to this stage the environment was changed by the citric acid cycle precursors. A fragment
that geochemistry began to take on the accumulation of a destructive toxin— of that detailed chart is shown in Figure
features of replication and selection oxygen—that was produced by pri- 4. The innermost layer consists of mol-
ecules that can be built from cycle in-
termediates with one chemical reaction,
the next layer consists of those that can
be built with two reactions, and so on.
(Once you get past the first few layers,
the counting becomes ambiguous, as the
reactions often involve molecules that
were themselves the products of layers
farther in).
From this layered structure we be-
lieve we can see the chemical cascade
that comprised the earliest steps in the
evolution of life.
QSPQBOBM The primordial core chart is simpler
than the elaborate chart made by com-
bining organisms today, but it is not
much simpler biosynthetically. It con-
tains the major modules for sugars, oils
and amino and nucleic acids, and we
have proposed that it was—at least in
QSPQFOBM broad outline—the agency of chemical
selection in an era that preceded natural
selection on distinguishable organisms.
Figure 5. PRIMOS—the Prebiotic Interstellar Molecule Survey—has focused on Sagittarius
B2(N), a cloud near the center of our galaxy (left, radio telescope image top right). The radio If this notion turns out to be true, it
footprints of many organic molecules have been detected there (bottom right). Where aqueous will have important implications for a
carbon chemistry occurs, is metabolism far behind? (Image (left) courtesy of NASA and The deep philosophical question: whether
Hubble Heritage Team (STScI/AURA); Image (top right) courtesy of Gaume, R., et al. 1995. As- we should understand the history of
trophysics Journal 449:663, reprinted by permission of the American Astronomical Society.) life in terms of the working out of pre-

BDFUBUF with permission only. Contact perms@amsci.org.
dictable physical principles or of the “of a state” if the state depends for its supposing that a few large RNA mol-
agency of chance. We are, in fact, argu- context on a process of change; only the ecules control the adaptation of a pas-
ing that life will appear on any planet entropy of the whole process is expected sive small-molecule reaction network,
that reproduces the environmental and to be maximized. To return to our pond Copley supposes that whole networks
geological conditions that appeared on on the hill, there is not a separate entropy of intermediate molecules support each
the early Earth, and that it will appear of the pond, except as an approximation. other on the path toward complexity. In
in order to solve precisely the sort of Rather, there is an entropy of paths of this experimental setting, networks of
”stranded electron” problem discussed change that include pond, channel, con- small and randomly synthesized ami-
above. The currently popular view that struction and relaxation. When such a no acids and single RNA units aid each
complex life was something of a fro- formulation is analyzed for a simple sys- others’ formation, assembly into strings
zen accident was set forth in Jacques tem, the establishment of a channel can and evolution of catalytic capacity. Both
Monod’s classic book Chance and Neces- be seen as a phase transition, similar to types of molecules grow long together.
sity (1970). We, of course, are arguing the the freezing of an ice cube or, to use a Complexity, adaptation and control are
opposite, if only for a significant part of more precise mathematical analogy, the distributed in such networks, rather than
basic chemical architecture. (It is impor- formation of a magnet from molten iron. concentrated in one molecular species
tant to appreciate that Monod studied (In the latter case, the phase transition oc- or reaction type. Distributed control is
regulatory systems, and in the domain curs as the metal cools when the atomic likely to be a central paradigm in the
of his expertise, we recognize the im- dipole magnets line up in the same di- development of Metabolism First as a vi-
portance of accident, though we believe rection—paradoxically, a more ordered able theory. We eagerly anticipate more
he advocated it too broadly.) It has not state). The full entropy of the process will experimental efforts like these to explore
escaped our notice that the mechanism be maximized in the system, even though the many facets of small-molecule sys-
we are postulating immediately suggests the approximate entropy associated with tem organization.
that life is widespread in the universe, the “state” of the channel may not be, In a larger sense, however, the future
and can be expected to develop on any thereby eliminating the paradox. of the experimental program associated
planet whose chemistry resembles that Current research into this foundational with the Metabolism First philosophy
of the early Earth. question now centers on the fact that the is tied to the development of the appro-
The view of life originating as a net- chemical substrate of living systems is priate theory, guided by experimental
work of simple chemical reactions will much more complex than that of simple results. The hope is that the interplay
require a lot of testing before it is adopt- physical systems that have been exam- of theory and experiment, so familiar
ed by the scientific community. We iden- ined so far. One important new direction to historians of science, will produce a
tify two areas where research is being of research involves the development of theory that illuminates the physical prin-
pursued: the development of the theory small-molecule catalysts in increasing- ciples that led to the development of life
of nonequilibrium statistical mechanics ly complex cooperative networks. The and, hence, give us the ability to re-create
and the experimental pursuit of those hope is that when a full theory is avail- life in our laboratories.
first nonenzymatic chemical reactions able, we will see the formation of life as Assuming the experimental and theo-
that led to modern life. an inevitable outcome of basic thermo- retical programs outlined above work
On the theoretical side, we have to dynamics, like the freezing of ice cubes out well, our picture of life as a robust,
start with the realization that if we apply or the formation of magnets. inevitable outcome of certain geochem-
standard equilibrium thermodynamics On the experimental side, some re- ical processes will be on firm footing.
to living systems, we arrive at something searchers, such as George Cody at the Who knows? Maybe then someone will
of a paradox. Living systems possess Carnegie Institution of Washington, write a book titled Necessity, Not Chance.
low entropy, which makes them very D.C., are trying to work out the basic
improbable from the equilibrium ther- rules of organic chemistry for exotic Bibliography
modynamic viewpoint. From the point environments that might have been Morowitz, H. J. 1999. A theory of biochemi-
of view of theoretical physics, the basic relevant to the origin of life. Cody, for cal organization, metabolic pathways, and
evolution. Complexity 4:39–53
problem is that classical thermodynam- example, has worked on unraveling or-
Smith, E., and H. J. Morowitz. 2004. Universal-
ics has only been well developed for sys- ganic interactions at the kinds of tem- ity in intermediary metabolism. Proceed-
tems in equilibrium—systems that do peratures and pressures that obtain at ings of the National Academy of Sciences of the
not change over time—or that change deep ocean vents. Mike Russell at the U.S.A. 101:13168–13173.
only by moving through successive, in- Jet Propulsion Laboratory in Pasadena, Morowitz, H. J., and E. Smith. 2007. Energy
finitesimally different equilibrium states. California, (author of “First Life,” Janu- flow and the organization of life. Complexity
13:51–59.
What is needed, therefore, is an exten- ary–February 2006) is building a large
Srinivasan, V., and H. J. Morowitz. 2009. The ca-
sion of ordinary thermodynamics so that chamber to model the geochemistry of nonical network of autotrophic intermediary
it can apply to systems maintained far those environments. Shelley Copley at metabolism. Biological Bulletin. In Press.
from equilibrium by the flow of energy. the University of Colorado at Boulder
One promising approach was first sug- has been sorting out the intermediate
gested by E. T. Jaynes in the mid-20th chemistry leading to the current nucle-
century. He recognized that information ic acid–protein system of genetic cod- For relevant Web links, consult this
(and hence entropy) is associated not just ing, with an eye toward resolving the issue of American Scientist Online:
with states but with whole histories of chicken-and-egg problem. These experi-
http://www.americanscientist.org/
change, which can include channel flows ments represent a major paradigm shift
issues/id.78/past.aspx
of the sort we have been discussing. Tech- from the top-down control envisioned
nically, one cannot talk about the entropy in RNA World scenarios. Rather than


Origin of Life

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Origin of Life

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A reprint from

The Origin of Life

James Trefil, Harold J. Morowitz and Eric Smith

A s the frontiers of knowledge have

© 2009 Sigma Xi, The Scientific Research Society. Reproduction

© 2009 Sigma Xi, The Scientific Research Society. Reproduction

© 2009 Sigma Xi, The Scientific Research Society. Reproduction

© 2009 Sigma Xi, The Scientific Research Society. Reproduction

© 2009 Sigma Xi, The Scientific Research Society. Reproduction

© 2009 Sigma Xi, The Scientific Research Society. Reproduction

© 2009 Sigma Xi, The Scientific Research Society. Reproduction

© 2009 Sigma Xi, The Scientific Research Society. Reproduction

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