by Charles Baum
shied away from the origins field in the beginning, when it held a
rather dubious status in science. Everyone is interested in how life
began, to be sure, but unambiguous experiments and firm con-
clusions are scarce. It was hard enough for many women to be
taken seriously as scientists in the 1950s, 1960s, and even into
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GENESIS
the 1970s. No point in stacking the deck by entering a suspect
area of research. Better to have concentrated on mainstream sub-
jects like genetics or organic chemistry if you wanted to land a
good job.
Times have changed. More than 100 women scientists par-
ticipated in the 2002 Astrobiology Science Conference at NASA
Ames, while female enrollments in several astrobiology PhD pro-
grams are close to 50 percent. But our community must still look
in the mirror and ask why it has taken so long.
Part IV
The Emergence of
Self-Replicating Systems
Four billion years ago, life began to emerge on an Earth hellish al-
most beyond imagining. Volcanoes poured rivers of lava onto the
land and belched noxious sulfurous vapors into the atmosphere, while
meteors fell in a fitful bombardment. Violent weather and epic tides
lashed the primordial coastlines. Nothing remotely lifelike graced the
desolate surface.
Yet the seeds of life had been planted. The Archean Earth boasted
vast repositories of serviceable organic molecules that had emerged
from chemical reactions in the sunlit oceans and atmosphere, the
depths of the crust, and the distant reaches of space. These molecules
inevitably concentrated and assembled into vesicles, polymers,
and other macromolecules of biological interest. Yet accumulations
of organic macromolecules, no matter how highly selected and intri-
cately organized, are not alive unless they also possess the ability to
reproduce.
Most experts agree that life can be defined as a chemical phenom-
enon possessing three fundamental attributes: the ability to grow, the
ability to reproduce, and the ability to evolve. The first of these three
characteristics, individual cell growth, has occurred on an all but invis-
ible scale for most of Earth’s history; for 3 billion years—from about
3.8 billion years ago to about 700 million years ago—the largest living
organisms on Earth were microscopic single-celled objects. The third
characteristic, evolution, proved to be slow and subtle: It took billions
of years for cells to learn some of the most familiar biochemical tasks,
such as using sunlight for energy or oxygen for respiration. But repro-
duction, life’s most dynamic overriding imperative, must have oper-
ated with an inexorable, geometric swiftness. In the geological blink of
an eye, rapidly reproducing populations of cells doubled and re-
doubled, spreading through Earth’s oceans, colonizing and transform-
ing the globe. Reproduction, more than any other characteristic of life,
set the world of life apart from the prebiotic era.
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GENESIS
For origin-of-life researchers, creating a self-replicating molecular
system in a test tube has become the experimental Holy Grail. It has
proved vastly more difficult to devise an experiment to study chemical
self-replication than to simulate the earlier stages of life’s emergence—
prebiotic synthesis of biomolecules, or the selective concentration and
organization of those molecules into membranes and polymers, for
example. In a reproducing chemical system, one small group of mol-
ecules must multiply again and again at the expense of other mol-
ecules, which serve as food. It’s an extraordinarily difficult chemical
feat, but the rewards for success are immense. Imagine being the first
scientist to create a lifelike chemical system in the laboratory!
14
Wheels Within Wheels
The origin of metabolism is the next great virgin territory
which is waiting for experimental chemists to explore.
Freeman Dyson, Origins of Life, 1985
Scientists who study life’s origins divide into many camps. One
group of researchers claims that life is a cosmic imperative that
emerges anywhere in the universe if conditions are appropriate, while
their rivals view life on Earth as a chance (and probably unique) event.
One camp claims that some sort of enclosing membrane must have
preceded life; another counters with models of “flat” surface life. Some
researchers insist that life’s origin depended on solar energy, while oth-
ers point to Earth’s internal heat as a more likely triggering source.
Lacking adequate observational or experimental evidence to arbitrate
these divergent views, positions sometimes become polarized and in-
flexible.
Perhaps the most fundamental of the scientific debates on origin
events relates to the timing of two essential biological processes, me-
tabolism and genetics. Metabolism is the ability to manufacture
biomolecular structures from a source of energy (such as sunlight) and
matter scavenged from the surroundings (usually in the form of small
molecules). An organism can’t survive and grow without an adequate
supply of energy and matter. Genetics, by contrast, deals with the trans-
fer of biological information from one generation to the next—a blue-
print for life via the mechanisms of information-rich polymers, such
as DNA and RNA. An organism can’t reproduce without a reliable
means to pass on its genetic information.
The problem as it relates to origins is that metabolism and genet-
ics constitute two separate, chemically distinct systems in today’s cells,
191
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GENESIS
much as your circulatory and nervous systems are physically distinct
networks in your body. Nevertheless, just like your blood and your
brains, metabolism and genetics are inextricably linked in modern life.
DNA holds genetic instructions to make hundreds of molecules essen-
tial to metabolism, while metabolism provides both the energy and the
basic building blocks to make DNA and other genetic materials. Like
the dilemma of the chicken and the egg, it’s difficult to imagine a time
when metabolism and genetics were not intertwined. Consequently,
origin-of-life researchers engage in an intense ongoing debate about
whether these two aspects of life arose simultaneously or independently
and, if the latter, which one came first.
Most experts seem to agree that the simultaneous emergence of
metabolism and genetics is unlikely. The chemical processes are just
too different, and they rely on completely different sets of molecules.
It’s much easier to imagine life arising one small step at a time, but
what is the sequence of emergent steps?
Those who favor genetics as the first step argue in part on the basis
of life’s incredible complexity. They point to the astonishing intricacy
of even the simplest living cell. Without a genetic mechanism, there
would be no way to
ensure the faithful reproduction of all that com-
plexity. Metabolism without genetics, they say, is nothing more than a
bunch of overactive chemicals. Biologists, who must deal with com-
plex cells and whose academic curriculum is dominated by the power-
ful, unifying spell of the genetic code, seem inclined to adopt this view
without reservation.
Other scientists, myself included, tend to be more influenced by
what we perceive as the underlying chemical simplicity of primitive
metabolism. We are persuaded by the principle that life emerged
through stages of increasing complexity. Metabolic chemistry, at its
core, is vastly simpler than genetics, because it requires relatively few
small molecules working in concert to duplicate themselves. Harold
Morowitz and Günter Wächtershäuser, among others, agree that the
core metabolic cycle—the citric acid cycle, which lies at the heart of
every modern cell’s metabolic processes—survives as a chemical fossil
almost from life’s beginning. This comparatively simple chemical cycle
is an engine that can bootstrap all of life’s biochemistry, including the
key molecules of genetics.
We conclude that if life arose through a sequence of ever more
complex emergent steps, then bare-bones metabolism seems the more
WHEELS WITHIN WHEELS
193
likely precursor. Such a no-frills metabolic system, furthermore, might
easily be enclosed in a primitive membrane of the type David Deamer
makes in his lab. My sense is that many chemists, physicists, and geolo-
gists (not many of whom deal with DNA on a regular basis) are per-
suaded by this metabolism-first point of view.
Origin-of-life scientists aren’t shy about voicing their opinions on
the metabolism-first versus genetics-first problem, which will prob-
ably remain one of the hottest controversies in the field for some time.
Meanwhile, as this debate fuels animated discussions at conferences
and in print, several groups of researchers are attempting to shed light
on the issue by devising self-replicating chemical systems—metabo-
lism in a test tube.
SELF-REPLICATING MOLECULES
The simplest imaginable self-replicating system consists of a single
molecule that makes copies of itself. In the right chemical environ-
ment, such an isolated molecule will become two, then four, then eight
molecules and so on in a geometrical expansion. Such a molecule is
autocatalytic—that is, it acts as a template that attracts and assembles
its own components from an appropriate chemical broth. Single self-
replicating molecules are intrinsically complex in structure, but or-
Self-replicating molecules catalyze their own formation from smaller building blocks.
In this example, one molecule AB plus individual A and B molecules combine to
make new AB molecules.
194
GENESIS
ganic chemists have managed to devise several varieties of these curi-
ous beasts.
Self-replicating molecules possess a distinctive feature known as
self-complementarity. Pairs of complementary molecules—molecules
of different species that fit snugly together because of their shape and
the arrangement of their chemical bonds—turn out to be relatively
common in nature. Many of the proteins in your body, for example,
function because they are complementary to food, neurotransmitters,
toxins, or other molecules of biological importance. For this very rea-
son, the synthesis of complementary molecules has become a central
task of computer-aided drug design. If you can design a molecule
that fits into pain receptors and thereby blocks pain signals, you can
make a lot of money. Only a handful of known molecules are self-
complementary, however, and even fewer can self-replicate.
Hungarian-born chemist Julius Rebek, Jr., now at the Scripps Re-
search Institute in La Jolla, California, has spent many years designing
such molecules. In 1989 Rebek’s group employed three smaller mol-
ecules: the purine adenine; the two-ring cyclic molecule napthalene;
and imide, a nitrogen-containing compound. When bonded end-to-
end, the resulting adenine–napthalene–imide molecule is self-comple-
mentary and, if immersed in a solution containing lots of these three
individual molecules, will make copies of itself.
Reza Ghadiri, leader of another productive research group at
the Scripps Institute, focuses on yet another chemical system—self-
replicating peptides, which are arguably much more relevant than most
other molecules when it comes to the origin of life. Peptides, like pro-
teins, are chainlike molecules built from long sequences of amino ac-
ids; their constituents are drawn from the same library of 20 amino
acids that make up proteins, but they are typically dozens instead of
hundreds of amino acids long. In 1996, Ghadiri’s group reported the
first synthesis of a self-replicating peptide—a sequence of 32 amino
acids. For self-replication to occur, however, this peptide had to be “fed”
two reactive fragments, one of them 15 and the other 17 amino acids
long. Given a steady supply of these two precursor fragments, new pep-
tides formed spontaneously.
Self-complementary strands of the genetic molecule DNA display
similar self-replicating behavior. As James Watson and Francis Crick
famously discovered in 1953, the classic double-helix structure of the
DNA molecule is like a long, twisted ladder, whose vertical supports
WHEELS WITHIN WHEELS
195
are chains of alternating phosphate and sugar molecules and whose
rungs consist of the complementary pairs of molecules called bases:
Cytosine (C) always pairs with guanine (G), while adenine (A) always
pairs with thymine (T). Consequently, a single DNA strand with the
base sequence ACGTTTCCA, say, is complementary to a second single
The double-helix structure of DNA features two complementary sequences of the
bases A, C, G, and T. A always binds to T, while C always binds to G. The molecule replicates by splitting down the middle and adding new bases to each side. Thus, one strand becomes two.
196
GENESIS
strand TGCAAAGGT. When the two strands separate, each can then
make a copy of the original double helix—as noted in one of the most
celebrated and oft-quoted sentences in the history of biology, from
Watson and Crick’s landmark paper: “It has not escaped our attention
that the specific pairing we have postulated immediately suggests a
possible copying mechanism for the genetic material.”
The vast majority of DNA strands are not self-complementary,
because the two halves of the double helix have different base se-
quences. But in 1986, German chemist Guenter von Kiedrowski and
co-workers synthesized the first of the so-called “palindromic,” self-
complementary DNA strands—the six-nucleotide sequence CCGCGG,
which makes exact copies of itself if sufficient supplies of fresh C and
G are provided.
It seems almost magical for a molecule to make copies of itself.
Nevertheless, th
ese self-replicating macromolecules do not meet the
minimum requirements for life on at least two counts. First, such sys-
tems require a steady input of smaller highly specialized molecules—
synthetic chemicals that must be supplied to the system from
somewhere. Under no plausible natural environment could sufficient
numbers of these component molecules have arisen independently.
Furthermore—and this is a key point in distinguishing life from non-
life—self-replicating molecules do not change and evolve, any more
than a photocopy can evolve from an original.
SELF-REPLICATING MOLECULAR SYSTEMS
More relevant to metabolism are systems of two or more molecules
that form a self-replicating cycle or network. Such systems are now the
subject of intense research, and a variety of strategies for molecular
self-replication have been identified. In the simplest so-called “cross-
catalytic” system, two molecules (call them AA and BB) form from
smaller feedstock molecules A and B. If AA catalyzes the formation of
BB, and BB in turn catalyzes the formation of AA, then the system will
sustain itself as long as researchers maintain a reliable supply of food
molecules A and B.
It’s easy for theorists to elaborate on such a model. Rather than
two cross-catalytic molecules, imagine a system with 10 or 20 mol-
ecules, each of which promotes the production of another species in
the system. Santa Fe Institute theorist Stuart Kauffman points to such
WHEELS WITHIN WHEELS
197
A•A•BB
B•B•AA
AA•AB
+
+
B
A
A
B
BB
AA
In a cross-catalytic system, two different molecules (in this example designated AA and BB) catalyze the formation of each other. More complicated cross-catalytic systems with numerous molecules may have been the first self-replicating cycle on the early Earth.
“autocatalytic networks” as the most likely form of metabolic protolife,
since that’s exactly what modern life does. Given the complexity of
living cells, he proposes that the molecular repertoire of the first auto-
catalytic network might have to be expanded to as many as 20,000 dif-
ferent interacting molecular species. Accordingly, Kauffman drafts
complex spaghetti-like illustrations of hypothetical reactants, each