Biology 103
2001 First Web Report
On Serendip

"The secret of life" is what Francis Crick reportedly claimed to have found when he and James Watson proposed a double-helix structure that explained the capacity of genetic material to replicate itself through pair-bonding of nitrogenous bases. (1). Watson and Crick's explanation of how genetic material is copied did unravel one of life's most perplexing mysteries, but secrets remain -- including the most fundamental one: how did the elegant, complex structure Watson and Crick described get there in the first place?

Watson and Crick's work led to the development of the theory that has come to be described as the "central dogma" of molecular biology: genetic information flows from DNA, in the nucleus of each cell, to RNA, which carries the information out of the nucleus into the body of the cell and uses the instructions encoded in it to produce protein, the workhorse of the cell. (2).

The duplication of DNA isn't spontaneous or haphazard; it requires numerous enzymes to catalyze the chemical reactions that unwind the helix and string together the sugars, phosphates and bases that make up DNA. But the enzymes that catalyze those reactions are, of course, proteins -- the end products of the information coded in DNA. Proteins are enormously complex macromolecules that can only be produced from DNA's instructions. There can be no proteins without DNA, and there can be no DNA without proteins. So how did both end up in every living cell?

In the late 1960s, several biologists, including Crick, proposed a way out of this chicken-and-egg conundrum, speculating that the ancestor molecule was neither DNA nor a protein, but RNA, the versatile messenger molecule. RNA, they suggested, might have catalyzed reactions necessary for replication as well as providing the genetic information necessary to replicate itself. According to Leslie Orgel, one of those who suggested such a scenario, "There were a few reasons why we favored RNA over DNA as the originator of the genetic system, even though DNA is now the main repository of hereditary information. One consideration was that the ribonucleotides in RNA are more readily synthesized than are the deoxyribonucleotides in DNA. Moreover, it was easy to envision ways that DNA could evolve from RNA and then, being more stable, take over RNA's role as the guardian of heredity." (3).

But the hypothetical primordial RNA, Orgel and others said, would have to have properties not seen in the RNA of today, namely the ability to reproduce itself and the ability to catalyze every reaction necessary to protein synthesis. The theory of RNA as the original genetic material didn't really catch fire until the 1980s, when Thomas Cech and Sidney Altman independently discovered a kind of RNA that catalyzes a reaction -- it "splices" out the parts of a gene that have no function in protein coding. (4).

The discovery of this RNA enzyme, or ribozyme, revived interest in the earlier conjecture that RNA might have been the original, Jack-of-all-trades genetic material. In a 1986 article in Nature, Walter Gilbert outlined an evolutionary scenario he called the "RNA World," in which RNA molecules catalyze their own replications, then evolve to be able to undertake "a range of enzymatic activities, including the synthesis of proteins, and are finally superseded as the primary storehouse of genetic information by the much less versatile, but much more stable DNA, which is created by a process of reverse transcription. (5).

Since Cech and Altman were awarded the Nobel prize in 1989 for their discovery of enzyme catalysis, research into the RNA World theory has exploded. Researchers continue to discover new functions for existing RNA, illustrating repeatedly how versatile these molecules can be.(6).

And teams of graduate students all around the world are feverishly trying to illustrate how RNA might have evolved in a way that is consistent with Darwinian selection. In vitro evolution, a technique that involves the random generation of trillions of possible RNA sequences and selection of those that display catalytic properties, has resulted in self-replicating RNA.(7).

No RNA molecule long enough to encode an entire gene has yet been developed, however,(8) and the RNA World, although it seems to be a widely accepted account of the origin of self-replication, has its detractors. Among those who have reservations about the theory is Leslie Orgel, one of the scientists who first proposed it in the 1960s. While Orgel still thinks that RNA played an important role in the development of early life, he concedes that researchers who have attempted to illustrate the possibility of spontaneous generation of the chemical elements of RNA itself have had only modest success. Of particular concern is the fact that ribose, the sugar that is part of the backbone of the RNA molecule, is difficult to create from hypothetical early earth conditions except in very small quantities.(9).

Another objection to the RNA World theory is that even if RNA could have formed spontaneously, extreme conditions on the primitive Earth might have led to rapid chemical degradation of it. (10). The difficulties researchers have faced "do not completely rule out the possibility that RNA was initially synthesized and replicated by relatively uncomplicated processes," Orgel says, but they have led many theorists to consider the notion that that RNA "was not the first self-replicating molecule on the primitive earth - that a simpler replicating system came first."(11).

Several proposals for alternative, earlier genetic materials, have suggested molecules in which the bases characteristic of DNA and RNA -- whose complementary pairing ensures replication -- are attached to backbones made of compounds that differ slightly from the sugars present in modern DNA and RNA. One research group recently created a molecule they call TNA, which is built on a backbone of phosphates and threose, a sugar with four carbon atoms rather than the five of RNA's ribose or DNA's deoxyribose. TNA molecules pair up with DNA and RNA, making replication possible, but the development of a four-carbon sugar from two identical two-carbon units may be more plausible than unassisted synthesis of the five-carbon varieties in contemporary nucleic acids.(12).

Other researchers have focused on the indispensability of some kind of compartmentalization to the emergence of RNA-based life. As one prominent RNA World research group says, natural selection can't operate in the absence of compartmentalization because an RNA molecule that is especially efficient at replication will replicate other, less efficient types indiscriminately. Only if it is segregated from other RNAs by something like a membrane can natural selection confer reproductive advantage.(13).

NASA researchers have created a sort of proto-membrane in conditions that duplicated the conditions of interstellar space; they suggest that compounds formed in space could have been delivered to earth by comets, meteorites or interstellar dust.(14)

Others have pointed out that lipids, which can be relatively small and simple in the context of biological macromolecules, spontaneously form "membrane vesicles."(15)

A rare point of agreement about the RNA World is that no amount of research can actually prove that it ever existed: it can only suggest whether such a scenario was possible. And there seems to be no convergence towards agreement on fundamental principles. Molecular biologists who have spent untold hours researching and speculating about the RNA World hold opinions about the origin of life ranging from a solid belief that the evolution of life was the inevitable product of laws of nature"(16) to an equally firm conviction that it could not have happened without some kind of outside intervention. (17)

WWW Sources

2) MIT Biology Hypertextbook

3) Leslie Orgel, The Origin of Life on Earth,

4) Nobel Foundation Web site, 1989 press release

5) Brig Klyce, "The RNA World."

6) Ricki Lewis, "Scientists Debate RNA's Role at Beginning of Life on Earth," The Scientist, 3/31/97

7)MIT News Office, 1995 Press Release

8) Scott Strobel, "Biological catalysis: Repopulating the RNA World," Nature, 6/28/2001

9) Leslie Orgel, The Origin of Life on Earth

10) Sidney Altman, "The RNA World," Nobel Foundation Web site, 4/2/2001

11) Leslie Orgel, The Origin of Life on Earth

12) Scientific American, News in Brief, November 2000

13) Jack W. Szostak, David P. Bartel & P. Luigi Luisi< "Synthesizing Life, Nature, 1/18/2001

14) BBC News, 1/29/2001

15) Vincent P. Cirillo, lecture notes for Biology 1412, University of Texas at Dallas

16)Christian de Duve, "The Beginnings of Life on Earth," American Scientist, September-October 1995

17) Gordon C. Mills and Dean Kenyon, "The RNA Worls: A Critique"

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