Symposium Animates Origins of Life Initiative

On May 15, 1953, little more than a month after James Watson and Francis Crick published their brief paper on the structure of DNA, the journal Science ran an equally brief letter by a second-year graduate student, working in the lab of Nobel laureate Harold Urey. The student, Stanley Miller, reported that by sending a stream of electric sparks into a flask holding a mixture of gases thought to represent Earth’s primeval atmosphere, he had produced amino acids, the building blocks of life.

Photo by Justin Ide/Harvard News Office

“Playing around with soap and dirt”—fatty acids and clay—“we hope to derive some key components of potential early cells,” said Jack Szostak at the first symposium of the Harvard Origins of Life Initiative.

The Miller-Urey experiment, one of the most famous ever run, showed for the first time how inorganic chemicals might be converted into organic molecules. Now a more difficult problem loomed, namely, how did the primordial swirl of chemicals spontaneously give rise to Watson and Crick’s newly discovered self-replicating molecule, and also to RNA, and from there to cells with the power to grow and reproduce?

“What happened between the prebiotic soup and the RNA world? No one knows,” said Robert Hazen, research scientist at the Carnegie Institution of Washington. That may be about to change. Two years ago, a group of Harvard scientists, answering a University-wide call for interdisciplinary projects, proposed that the time was ripe to study the origins of life in the universe from a scientific perspective. Drawing together students of the infinite—astronomers and planetary scientists—and the infinitesimal—chemists and molecular biologists—would create the kind of synergy needed to answer the unsolved questions of how life began, they said. The Origins of Life Initiative has been funded and is already starting work.

“This is a remarkable intellectual feat,” said Steven Hyman, Harvard University provost, at the inaugural symposium, held on Nov. 8. Hazen was the keynote speaker at the event. What makes the endeavor even more noteworthy, Hyman said, is that Harvard is a famously decentralized institution with long-standing barriers to collaboration. “Natural science may be the most likely area for this since scientists will follow a problem wherever it leads,” he said.

Out of this World
Determining the origins of life is actually a series of problems, said Jack Szostak, HMS professor of genetics, and a leader of the initiative. Though his own focus is on how self-replicating molecules and cells evolved from complex chemicals on Earth, the initiative plans to look at other planets, such as Mars, and also beyond the solar system. “If you think about the origins of life, plural, you have to think about life in the context of the universe,” said Dmitri Sasselov, professor of astronomy at Harvard and director of the initiative. Over the past few years, he and his colleagues have discovered several Earth-like planets outside the solar system and hope that by studying these exoplanets, they will uncover general conditions under which life may begin, which can then be used by Szostak and others to understand the origins of life on Earth.

Though speakers at the symposium were clearly excited by the approach, they also acknowledged its limitations. “There is this piece of cumbersome equipment that we work with, the scientific method,” said George Whitesides, the Woodford L. and Ann A. Flowers University Professor in the Department of Chemistry and Chemical Biology. Life on Earth evolved billions of years ago and, short of a time machine, there is no way to falsify our hypotheses about how exactly it happened, he said. 

Darwinian Behavior
At their most basic, Earthlings exist as packets of genetic material surrounded by lipid membranes. Using these attributes as a starting point, Szostak told the audience of about 140 people, he and colleagues set out to create a stripped-down version of a living cell. “We want it to be able to grow and divide based solely on physical and chemical principles, with no preexisting biological machinery,” he said. “We are asking for replication to occur spontaneously and for daughter copies to be distributed equally.” Just as copying mistakes are made in living organisms, and can alter an organism’s fitness, so too the researchers hope variations will occur in their protocells. “That is the behavior that we really want to see, the spontaneous emergence of Darwinian properties,” he said.

That may seem a tall order, but Szostak said that his team has already made strides. Several years ago, the researchers showed that fatty acids can form a bilayer membrane that spontaneously closes up into a spherical structure, or vesicle, and that the size and rate of formation of vesicles can be altered by purely chemical and physical means, such as changes in pH and the addition of clay. By forcing large vesicles through a porous membrane, they created threadlike vesicles that could break, which might be a prerequisite for cell division.

On the genetic side of things, they have created elongated nucleic acid chains that can latch onto other chains and partially copy those chains. The researchers have begun to introduce these nucleic acid chains into their vesicles. In a series of experiments, they found that vesicles containing a lot of nucleic acid experience great osmotic pressure, which puts their membranes under tension. Tenser membranes can absorb fatty acids from less pressurized vesicles and grow. At some point, these growing cells might divide, which means that any nucleic acid that can replicate faster could take over. “That would be the emergence of Darwinian evolution at the cellular level,” Szostak said.

Of course, that does not mean it happened that way. “Jack says we may be on the brink of understanding the origin of life, but I am a little less convinced of that,” said Whitesides. “I think there may be some part of the story we do not know yet.” On the other hand, there may be too many pieces. Origins-of-life researchers focus on various aspects such as the primordial environment, chemicals, catalysts, and energy sources, but for each there is a multiplicity of possibilities. “Too many pathways to follow,” he said. Even if one were to winnow out a few possibilities, there would still be what he called the network problem.  “Life does not require a lot of reactions, but they need to be involved in a workable network.”

Making matters even more complex is the fact that once life arises, it alters the system. “Life is a planetary phenomenon, constraining the pathways that led to life,” said Sasselov. One way to get a handle on the problem is to compare the situation on Earth to other planets, some of which may offer a more pristine picture. Andrew Knoll, the Fisher professor of natural history and professor of earth and planetary sciences at Harvard, will be analyzing Mars sedimentary environments sent back by the Opportunity Rover. HMS professor of genetics Gary Ruvkun proposes to scour the Mars sediments for microbial genetic material using a very high-powered polymerase chain reaction (PCR) device.

“The next step is to go beyond the solar system,” said Sasselov. “We can look at the rich diversity of initial conditions and piece together origins this way.” So far, 209 small Earth-like planets have been discovered, several by Sasselov and colleagues. Yet studying Earth-like planets is difficult. They tend to be relatively small and too close to their suns to be clearly seen. Occasionally they pass in front of their parent star, obscuring it. Sasselov used this transit method to detect exoplanets. A highlight of the symposium was a live tie-in to a website showing the transit of Mercury across the face of the sun. In 2008, NASA will be launching the Kepler mission, a Discovery space vehicle equipped with a telescope for finding Earth-like planets using the transit method. Sasselov and colleagues are part of the mission. “We want to make Harvard a place where the first Earth-like planets are discovered and studied,” he said.

Other leaders of the Origins of Life Initiative at Harvard are Stein Jacobsen, professor of geochemistry; Myron Lecar, lecturer on astronomy; and Scot Martin, the Gordon McKay professor of environmental chemistry.

—Misia Landau

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