Look inside the machinery of a human cell and you would see that its
working parts are composed largely of proteins and its data storage is
handled by DNA. But look a little closer and a third agent seems to be
running many of the trickiest parts of the show.
That agent is a stubby tangle of a molecule, bristling with curlicues
and gnarled as a coelacanth. Like that ancient fish, it is a living
relic, yet its roots stretch deeper than the oldest fossils. There are
many reasons to suppose that RNA, or ribonucleic acid, lies
tantalizingly close to the origin of life.
RNA handles much of the information processing of cells, even though
its better-known chemical cousin, DNA, has been assigned the chore of
archive management. The machine tools that build cell's proteins are
also made largely of RNA. To those who wonder how the system got to be
that way, a compelling thought is that RNA must be the most ancient part
of the system, and everything else accreted around it. If so, the best
chance of understanding how life first arose on earth may be to
In "The RNA World," a book whose second edition was published
recently by the Cold Spring Harbor Laboratory on Long Island, some
leading experts on RNA peer as deeply as they can into the events of
some four billion years ago, when a bunch of molecules seem to have
dropped through the wormhole between two universes, from chemistry to
life. Much has been learned about RNA since the book's first edition in
1993, yet the new knowledge, rather than bolstering the theory of RNA's
leading role, seems to accentuate its difficulties.
A few years ago the full chemical structure of the DNA of a bacterium
was determined for the first time. The microbe, known as Haemophilus
influenzae, turned out to have 1,830,137 units of DNA, coding for 1,743
working parts, most of them proteins. That is a complex system but it
depends, like all today's living organisms, on just three principal
kinds of chemical: DNA and RNA for data processing, and proteins to
catalyze the required chemical reactions.
From the perspective of how life got started on earth, it seems
dauntingly unlikely that information-carrying molecules and
reaction-catalyzing molecules would emerge at the same time and place.
That impasse seemed to have been bridged with the discovery in 1982 that
certain kinds of RNA have catalytic properties. It followed that a
single RNA molecule could both carry information and catalyze
The concept of the RNA world, a phrase coined by Walter Gilbert of
Harvard, held that in the beginning there were no proteins and no DNA,
just RNA molecules that built more RNA molecules from chemical subunits
known as nucleotides.
"The first stage of evolution proceeds, then, by RNA molecules
performing the catalytic activities necessary to assemble themselves
from a nucleotide soup," Dr. Gilbert wrote in an essay of 1986. "The RNA
molecules evolve in self-replicating patterns, using recombination and
mutation to explore new functions and to adapt to new niches."
As the RNA molecules grew more capable, according to apostles of the
RNA theory, they deployed their catalytic properties to direct the
synthesis of proteins. The proteins, being more efficient catalysts,
took over the housework of the cell and DNA, a longer-lived molecule,
assumed the role of hard disk drive. If this conjecture is correct,
almost all that is left to explain about the origin of life is how the
first RNA molecules arose from the chemicals likely to have existed on
the primitive earth.
Nucleotides, the components from which RNA is made, consist of three
simple chemical units strung together -- a phosphate group, a sugar
known as ribose, and a sidechain ring of atoms known as a base. The
phosphates and bases are reasonably likely to have been present among
the chemicals on the early earth. For example adenine, one of the four
kinds of base, can be formed naturally from two common chemicals,
ammonia and hydrogen cyanide.
Ribose is more problematic. When formaldehyde, the simple chemical
from which sugars are likely to have been made, is brewed in suitable
conditions, it makes a syrup of sugars, only 2 percent of which is
ribose, an unpromising route to ribose nucleotides. But the chemist
Albert Eschenmoser recently found that if phosphate is added, the major
product of the brew is ribose phosphate.
Some biologists hope that with only a few more chemical surprises
like this, the problem of the origin of life will go away. But many
chemists are unconvinced. No one has yet figured out a way of loading
the bases onto ribose or ribose phosphate under the circumstances likely
to have prevailed four billion years ago.
Gerald F. Joyce of the Scripps Research Institute and Leslie E. Orgel
of the Salk Institute write in "The RNA World" that they believe the
appearance of small RNA molecules "would have been a near miracle."
Thomas R. Cech, an RNA expert at the University of Colorado, said in an
interview that RNA "is far too complex to have been the first
self-replicating molecule, as if it emerged like Athena from Zeus's
Both Dr. Cech and Dr. Orgel, a leading authority on the origin of
life, suggest that there was a pre-RNA world, in which the starring role
was played by some other self-replicating, catalytic molecule.
"We don't know what it was but we are looking," Dr. Orgel said.
Alternative genetic systems are now being studied. One, known as
pyranosyl-RNA, has a six-atom ring in place of the five-atom ring of
ordinary ribose. Another, called peptide nucleic acid, has the same
chemical backbone as proteins but with nucleic acid bases in place of
protein's usual amino acid side-chains.
Both pyranosyl-RNA and peptide nucleic acid display the behavior to
be expected of a genetic molecule, such as linking together in double
chains like the double helix of DNA.
"If you want DNA-like double helices, there are probably scores" of
molecules that would serve as genetic systems, Dr. Orgel said. "It
raises the question of why we have RNA and DNA instead of others that
are equally good."
The idea of a pre-RNA world creates many possibilities for
researchers exploring prebiotic reactions, the chemistry that led to the
first living entities. But in some ways it sets the search for the
origin of life back to square one. Pyranosyl-RNA and peptide nucleic
acid may be promising candidates, but no one yet knows if their
spontaneous formation is any more plausible than that of RNA.
The concept of the RNA world is also unproven in its central
assertion, that an RNA molecule could catalyze its own replication. The
natural RNA catalysts found today sponsor quite simple chemical
reactions. Chemists like David P. Bartel of the Whitehead Institute in
Cambridge, Mass., have been trying to construct RNA molecules with a
more extensive repertoire. Some RNA's show promising behavior such as
being able to copy a short stretch of another RNA. But that is a far cry
from a self-copying molecule.
"No one has come close to getting a self-replicating RNA," Dr. Bartel
said. "It's a long road. It would be exciting to get an RNA that can
copy a complete turn of the helix."
Another worry for prebiotic chemists is the possibility that they may
run out of time. Scientists once thought that a billion years or so
elapsed before the first appearance of life on earth. But the earliest
date that life could have started has been pushed forward by planetary
astronomers. They believe that debris left over from the early solar
system would have continued to bombard the earth long after the planet's
formation some 4.6 billion years ago. The larger of these impacts would
have boiled off the early oceans into steam, sterilizing the planet of
any life forms that might have emerged.
The primeval bombardment is thought to have ceased some four billion
years ago. Meanwhile, fossil hunters have steadily pushed back the date
by which life must have started by finding ever older fossils. The
earliest known fossils exist in rocks that are 3.85 billion years old,
leaving a mere 150 million years for life to have started.
This sharply narrower window is not yet an intellectual embarrassment
-- a lot can happen in 150 million years. Still, the shrinking window
worries the eminent theoretician of molecular biology, Francis H. C.
In a foreword to the first edition of "The RNA World," written when
the oldest known fossils were a mere 3.6 billion years old, Dr. Crick
said that the available window "leaves an astonishingly short time to
get life started." He also noted that the three kingdoms of early life
-- bacteria, the bacteria-like microbes known as archaea, and the plant
and animal kingdom -- "seem a very long distance from their hypothetical
Dr. Crick then proposed that life might have started elsewhere in the
universe, maybe on a planet whose chemical environment was more
conducive to the genesis of life than was Earth's. The three kingdoms
might represent the survivors of an assortment of microbes sent to
colonize distant planets.
Dr. Crick's speculation that life originated elsewhere would provide
an escape hatch for scientists trying to explain the origin of life on
earth should the available window of time be squeezed implausibly short.
So far the idea has few takers, but nor is it being dismissed out of
Dr. Orgel believes there is no way of assessing the probability of
life or how many years may have been required for its emergence. "It's
hard to say whether the origin of life took a million years or a
billion," he said. "I don't think there is anything to be concerned
about unless there were organisms extant before the earth became
inhabitable. That would be a real puzzle."
Dr. Cech agrees that life on earth got started astonishingly quickly,
but still looks to explain that process in terrestrial terms. "While
extraterrestrial origins cannot and should be discounted -- a lot of
organic material certainly came in via comets, for example -- it may not
be necessary to invoke 'visitors from outer space,' " he said.
In an experiment of 1953, still taught in every textbook, Stanley
Miller showed that several of the principal chemicals of life could be
formed by running an electrical discharge (lightning) through a flask of
air and water (atmosphere and ocean). At once the problem of the origin
of life seemed soluble in principle. But Dr. Miller's brilliant
experiment has proved something of a dead end; no one has managed to
take it much further.
The concept of the RNA world may be the best available scenario of
how life started, but as with Dr. Miller's experiment, it has proved
frustratingly difficult to take a promising idea further. "It would be
unhealthy not to have doubts," Dr. Cech said. "Scientists are good at
checking things in the lab, but this is a historical question and there
is no videotape to document what happened." However soluble the
mystery of life's origins may seem in principle, it remains very far
GRAPHIC: Chart: "Best Scenario for Origin of Life"
Life presumably evolved from the simple chemicals present on the
primitive earth some four billion years ago. The most likely scenario
focuses on ribonucleic acid, or RNA, a sub-stance that performs many
vital tasks in living cells today.
Nucleotides, the building blocks of RNA, consist of the sugar known as
ribose (R), attached to phosphate (P) and to a base (B). Each of these
three components can be made from simple chemicals like formaldehyde,
hydrogen cyanide and ammonia.
The probability that RNA molecules formed spontaneously on the primitive
earth seems very small at present. Maybe some other molecule gave rise
to RNA. But once in existence, an RNA molecule could both store
information and make copies of itself.
The self-copying RNA molecules somehow acquired a cell membrane. The
information-storage task was handed off to DNA and the job of catalyzing
chemical reactions passed to proteins. RNA continued many data
processing tasks. Today's cells are run by the troika of RNA, DNA and
protein. (pg. F4)