Leslie Orgel, the Salk Institute theoretical chemist who was the father of the RNA world theory of the origin of life and who joined with Nobel laureate Francis Crick to postulate that life might have been seeded on Earth by a higher intelligence, died at the San Diego Hospice & Palliative Care on Oct. 27 from pancreatic cancer. He was 80.
Reasoning that DNA was too complex to have been the first repository of genetic information, Orgel and others speculated that RNA could have preceded it, simplifying the evolutionary process. Even RNA is very complicated, however, so he also synthesized simpler molecules that could have arisen even before it.
"He would go for the fundamental questions of biology -- why is biology the way it is and how did it get there?" said Gerald Joyce, a biochemist at the Scripps Research Institute in La Jolla, who earned a doctorate with Orgel in the mid-1980s. "He's tackled every problem on the origins of life."
Orgel believed that "evolution was always one of the interesting mysteries of science," recalled molecular biologist Inder M. Verma, a Salk professor. "If we didn't know about evolution, how would we know anything about biology?"
While others in Salk's Chemical Evolution Laboratory were trying to mimic the environmental conditions under which the first amino acids and other biological molecules could have formed roughly 4 billion years ago, Orgel turned his substantial intellect to the problem of the development of molecules that could carry genetic information.
At the beginning of the 1960s, most scientists still believed that DNA, which is the ultimate repository of genetic blueprints, was the first such storage molecule to have evolved. Orgel, however, thought DNA was far too complex.
He noted that information contained in DNA was necessary to make proteins, the large molecules that carry out most cellular activities. But proteins are also necessary to make DNA, producing what he termed a "chicken and egg" conundrum: Which came first?
Experiments in the early 1960s suggested that RNA, which carries genetic information from DNA to the cells' protein-making machinery, could function as both a genetic repository and as an enzyme.
That versatility, combined with RNA's slightly simpler structure than DNA, hinted that it could have been the first large biological molecule to evolve, Orgel theorized. The primitive environment would thus have been an RNA world rather than today's DNA world, he said.
Similar proposals were put forward by Crick and by microbiologist Carl Woese, and the idea eventually became widely accepted. DNA, the theory held, would have evolved later because it is more stable, and thus would have been better for long-term storage of genetic information.
Orgel summarized the arguments for an RNA world in his 1973 book "The Origins of Life: Molecules and Natural Selection."
"Before life as we know it -- which is DNA genes and protein enzymes -- there literally was a different life form on this planet: RNA-based life forms. We are descendants of a different life form," Joyce said. "This is almost universally accepted now."
Experiments by other researchers during the 1970s, however, showed that it was very difficult to produce RNA under the primordial conditions of early Earth.
The primary reason, Orgel speculated, was that ribose, the sugar component that forms the backbone of RNA, was not sufficiently stable to survive the low oxygen and high radiation conditions then prevailing.
He thus began to look for simpler "backbone" molecules that could have formed more easily and survived longer in the primordial environment. His team produced a compound known as peptide nucleic acid, which is much simpler than RNA and that could copy itself in the test tube.
Although it probably was not the original genetic material, the work showed that the evolution of a more complex, self-replicating molecule from a simpler precursor was at least possible.
One side benefit of this work was researchers' discovery of a straightforward way to synthesize cytosine arabinoside, a compound that is one of today's most commonly used anti-cancer agents.
Ever one to consider a wide range of theoretical possibilities, Orgel mused about how a universal genetic code could have evolved. He and Crick proposed that it might have been brought to Earth by an extraterrestrial intelligence, a process called directed panspermia.
In an article in the journal Icarus, they said that while it was possible that life reached Earth in this way, the scientific evidence for it was so inadequate that no one could say anything about the probability.
Critics charged that the idea simply shifted the need for the evolution of DNA from Earth to some other place in the universe and thus did not really provide any solutions to the origin of life.
"It was done in the gesture of something exciting and novel," Verma said. "He was trying to be provocative."