A well-known problem of the ΛCDM model is the tension between the relatively high level of clustering, as quantified by the parameter σ8, found in cosmic microwave background experiments and the smaller one obtained from large-scale observations in the late Universe. In this paper we show that coupled quintessence, i.e. a single dark energy scalar field conformally coupled to dark matter through a constant coupling, can solve this problem if the background is taken to be identical to the ΛCDM one. We show that two competing effects arise. On one hand, the additional scalar force is attractive, and is therefore expected to increase the clustering. On the other, in order to obtain the same background as ΛCDM, coupled quintessence must have a smaller amount of dark matter near the present epoch. We show that the second effect is dominating today and leads to an overall slower growth. Comparing to redshift distortion data, we find that coupled quintessence with ΛCDM background solves the tension between early and late clustering. We find for the coupling β and for σ8 the best fit values β=±0.079+0.016-0.019 and σ8=0.818+0.028-0.028. These values also fit the lensing data from the KiDS-450 survey. We also estimate that the future missions SKA and Euclid will constrain β with an error of ± 7.2×10-4 and for σ8 of ± 8.0×10-4 at σ level.
Szostaks otte trin mod en udviklende RNA protocelle.
The origin of life remains a daunting mystery in part because rather than knowing too little, we increasingly know about too many possible mechanisms that might have led to the self-sustaining replication of nucleic acids and the cellularization of genetic material that is the basis of life on Earth.
Initial insights that biological compounds could be generated by prebiotic means quickly ran up against a gap in our understanding of how unguided syntheses could result in defined templates for replication. For example, the proposed prebiotic formose reaction for the synthesis of the ribose sugar in nucleic acids from formaldehyde produces little more than intractable tars. How ribose might be produced in higher yields turned out to involve both clever synthetic transformations and synthetic adjuncts, in the form of minerals such as boron and molybdenum. Nonetheless, speculation that a boron-rich environment, such as Mars, may have initially resulted in life arising and then being seeded to Earth merely moved prebiotic chemistry off-planet without dispelling our ignorance regarding which of the many possible pathways actually led to life.
It is possible that it is not a knowledge of prebiotic synthesis that is wanting, but knowledge of prebiotic replication. Simple organic replicators can be generated with varying degrees of efficiency and fidelity, and it is easy to imagine how such simple replicators might have evolved in complexity. However, what remains unknown is the degree to which the replication cycle would have led to the purification of materials (such as ribose) from otherwise complex mixtures of prebiotic chemicals. For example, it has been argued that enantiomerically pure nucleic acids would have served as better substrates for short replicators than impure ones, in part because the ability to form tight bonds with a nascent template would have been improved. In contrast, the argument can also be made that some mismatches in template-substrate pairings would have led to more robust replicators.
Once an early replicator established itself, and assuming that it selfishly favored chemically pure oligonucleotides or other substrates, the feedback cycle leading to the evolution of additional catalysts would have been difficult to derail. Ribozymes have been crafted that make carbon-carbon bonds, glycosidic bonds, phosphodiester bonds, and others, and it is possible that prebiotic analogs of these enzymes might have assisted in chemical syntheses in such an “RNA world” [a term originally credited to Gilbert]. Biochemistry occurred on geochemical time scales, in which millions of years of a poor replicator (a blink on the geological time scale) might well have been necessary to craft a feedback cycle that led to a slightly better replicator, or to a replicator that could better feed itself by directing the chemistry around it. Of course, none of these speculations even touches on key issues relative to surface chemistry and nascent cellularizations.
We don’t need to displace prebiotic chemistry to Mars in order to have a well-defined path to life. Although there are many illdefined paths (in some ways all equally plausible and all equally implausible) to life on Earth, recent research has begun to expand the likelihood of several of these paths. Primordial carbon fixation pathways, reminiscent of reactions found in extant methanotrophs, have been proposed in “metabolism-first” models of chemical evolution. By concentrating the necessary ingredients of life in compartments near hydrothermal vents, it may not be necessary to hypothesize reactions specific to martian deserts and the scarce methane atmosphere of a Hadean planet.
Once at least some metabolites become available and templates of whatever sort arise, the chance of “kick-starting” self-polymerizing ribozymes is an increasingly realistic option. A complex ribozyme ligase has been engineered to serve as a limited ribozyme polymerase capable of generating RNA transcripts long enough to have their own catalytic activity. This is not quite a demonstration of a self-replicase, but it nonetheless provides a means for understanding how the raw material of ribose-based life could have begun to accumulate. Similarly, oligonucleotides not much longer than those transcribed by the polymerase ribozyme can self-ligate in an exponential amplification cycle. When coupled with the demonstration that RNA oligonucleotides can self-assemble into autocatalytic networks, an origin can be imagined that involves the accumulation of short oligonucleotides by polymerization and ligation, and the parallel self-assembly of autocatalytic networks of longer enzymes that assisted with polymerization and ligation. Ultimately, a fully functional RNA polymerase should evolve from the heady broth of reactions in the primordial soup.
We on Earth are still left with a distinct lack of prebiotically synthesized, ribose-based oligonucleotides to feed the RNA world. But, as previously noted, we don’t necessarily have to start with ribose. Several lines of evidence suggest that backbone and linkage heterogeneities, once considered problematic in early synthesis strategies, are permissible in functional RNAs. Ribozymes and aptamers have both been shown to tolerate such heterogeneity. Indeed, such a mixed pool may have afforded a selective advantage by lowering the melting temperatures needed to separate polymer strands. Such mixed pools may also be more accessible via other prebiotic synthesis pathways.
As RNA or an alternative precursor nucleic acid begins to self-replicate, protection from molecular parasites and the low concentrations of needed substrates become paramount in propagating chemical information content. Compartmentalization of the genetic/catalytic machinery would have necessarily been an early invention or co-option of a self-replicase. The demonstration of protocell division based on simple physical and chemical mechanisms lends credence to the idea that nucleic acid and vesicle replicators got together for mutual benefit.
The great benefit of the demonstration of prebiotic amino acid synthesis from a simple gas mix and an electrical spark was not that it was a cookbook for how things occurred, but rather that it was the identification of a plausible path to an origin of life that would continue to bear experimental fruit. So it is with the chemistry, catalysts, and self-reproducing networks of today. The demonstration of ribose formation under some prebiotic conditions does not necessarily mean that we have to punt to Mars, but rather that a problem once thought intractable is now yielding to broader scientific inquiry.
By Robert F. Service |
Like a pair of hands that appear as mirror images of one another, biomolecules, such as DNA and RNA, come in left-handed and right-handed forms. Normally, enzymes that recognize one mirror image form won’t touch the other. But researchers have isolated RNA enzymes, known as ribozymes, that synthesize RNAs of the opposite handedness. As esoteric as this may sound, similar mirror image–making RNAs may have played a role in the early evolution of life.
Researchers consider RNA a likely central figure in the origin of life. That’s because, like DNA, the molecule can store genetic information, and like proteins it can act as a chemical catalyst that speeds up normally slow reactions. Many researchers believe that life likely got its start in an “RNA world” where RNAs evolved to replicate other RNA molecules. In this scenario, the more specialized DNA and proteins arose later.
Like DNA, RNA is made up of four nucleotide bases, in this case the nucleotides abbreviated A, U, C, and G. When ribozymes copy RNA, they start with a single strand of RNA that they use as a template to form a strand containing the complementary bases. C is complementary to G, and A is complementary to U. So if a template strand with the letters ACCGU were placed in a test tube with individual nucleotides floating around, the complementary bases U, G, G, C, and A would grab onto their partners on the template strand. Then for these complementary bases to form an intact complementary RNA strand, the ribozyme would need to chemically weld the adjacent nucleotides together, much as boxcars next to one another must be linked together to form a train.
The difference between RNA nucleotides and boxcars, however, is that individual nucleotides can come in either right- or left-handed forms, known as D- and L-nucleotides, respectively. All naturally occurring RNAs today are D-RNAs, but researchers can create L-RNAs in the lab. Normally, a ribozyme containing D-nucleotides won’t touch L-nucleotides, and ribozymes containing L-nucleotides won’t touch D-nucleotides. But if an opposite-handed nucleotide in a would-be complementary strand twists just right, it can fool a ribozyme and get integrated into the growing strand—with drastic consequences. Thirty years ago, researchers including Gerald Joyce, then a graduate student at the Salk Institute for Biological Studies in San Diego, California, showed that if a nucleotide with the opposite handedness was incorporated into a growing D- or L-RNA complementary strand, it shut down all further growth. “It acted like poison,” says Joyce, who is now at the Scripps Research Institute in San Diego.
This discovery raised a conundrum for origin-of-life researchers that they’ve struggled with ever since. Before life got its start, D- and L-nucleotides would likely have been equally abundant in the primordial soup. If so, how would RNA enzymes ever have managed to get the RNA copying process going without it being poisoned?
Now, Joyce and his postdoc Jonathan Sczepanski have found a possible solution. Online this week in Nature, they show that by using a technique called test-tube evolution they were able to generate ribozymes capable of assembling RNA strands of the opposite handedness in the presence of a mixture of D- and L-RNA nucleotides. What’s more, when they started with a D-RNA ribozyme, they found that it preferred to work on an L-RNA template to synthesize an L-RNA complementary strand. Likewise, they prepared L-RNA ribozymes that synthesized D-RNA complementary strands from D-RNA templates. And both the D- and L-RNA ribozymes were able to make mirror image copies of themselves.
The ribozymes work this trick in an unconventional way, Joyce explains. Instead of recognizing where complementary RNA bases (say an A and a U) reach across the template and complementary strand to recognize one another, the enzymes recognize the overall shape of the assembling RNA bases on the complementary strand and link whatever pieces wind up next to each other.
“It’s a very exciting advance towards RNA-catalyzed RNA replication,” says Jack Szostak, an origin-of-life researcher at Harvard University who was not involved with the work. However, Szostak says, it still begs the question of where such D-RNA and L-RNA ribozymes would have come from in the first place.
The answer may be forever lost to history, Joyce says. But the new work does suggest that if these cross-copying ribozymes arose early on, they could have copied both mirror versions of RNA to propel the evolution of more complex RNAs. If one of those later, more complex RNAs—say a D-RNA—proved more capable, it could have encouraged the copying of its own kind, and promoted the single-handedness in nucleotides that we see today.
By Roland Pease |
Life on Earth is a paradox—to function, all organisms need energy. But to harness that energy, living creatures rely on enzymes that have evolved over billions of years to make possible everything from respiration to photosynthesis to DNA repair. So what came first, the enzyme or the organism? A new study suggests that the iron-and-sulfur clusters at the heart of many life-critical enzymes could have been floating around Earth’s primordial seas some 4 billion years ago, produced by nothing more than primitive biomolecules, iron salts, and a previously unknown ingredient—ultraviolet (UV) light.
“It’s intriguing,” says Robert Hazen, a geophysicist who studies interactions between the mineral and living worlds at the Carnegie Institution for Science’s Geophysical Laboratory in Washington, D.C. “[The development of iron-sulfide clusters] was likely an important step in life’s origins.”
Most research into life’s origins has focused on how organic building blocks, like amino acids and nucleic acids, arose and assembled themselves into proteins and RNA. Less studied is the genesis of iron-sulfur clusters, the active core in enzymes that drive almost every aspect of cellular chemistry. Genetic analysis suggests they’ve been around at least since the time of our last common ancestor. “I’ve never seen an organism that doesn’t depend on them,” says Sheref Mansy, a biochemist at the University of Trento in Italy who led the new work.
But modern metabolic reactions are carefully calibrated inside living cells, in the presence of oxygen. Neither condition would have existed on Earth without life.
To find out whether iron-sulfur clusters were a core ingredient for life from the start—or whether the first organisms got along fine without them—Mansy and his team recreated the conditions of early Earth in their lab. University of Trento biochemist Claudia Bonfio removed oxygen and mixed together a brew of iron and glutathione, a sulfur-containing peptide likely present in the prebiotic chemical soup. When the iron was in an oxidation state that predominated on early Earth, iron (II), nothing happened. But when Bonfio flicked on the lights, a transformation took place.
“After a few minutes you could start to see the formation of iron-sulfur clusters,” she says. In the presence of UV light, the solution went from violet to red, indicating that the iron and sulfur were reacting. “And if you waited longer,” she says, “more complex clusters formed that gave the solution a brown color.” The light was simultaneously freeing sulfur atoms from the peptides and oxidizing the iron—turning it into a form, iron (III), that could readily interact with the sulfur, the team reports this week in Nature Chemistry.
The team then tested more than 30 other potential compounds under different conditions, and found that the reactions also worked with simpler sulfur-containing molecules. Some of them even worked inside fatty acid vesicles, a laboratory stand-in for protocells. In most cases, the process was “strikingly similar” to the way iron-sulfur clusters synthesize in modern living cells, the authors write.
It makes sense, says Mansy, that sunlight would play a role in early iron-sulfur synthesis. That’s because Earth lacked an ozone layer to protect it from UV light—which was far more intense 4 billion years ago than it is now. What’s more, lakes all over young Earth would have hosted mineral-rich stews similar to those in the experiment. That’s particularly true for those inside volcanic craters and impact areas, where water moving through fractured rocks could bring iron to the surface, says Jack Szostak, a Harvard University molecular biologist who also took part in the work. Indeed, a paper by co-author John Sutherland—a chemist at the Medical Research Council Laboratory for Molecular Biology in Cambridge, U.K.—suggests that all the basic chemicals for life can be cooked up in a water-filled impact crater.
But Mansy himself is cautious about the new work’s significance. Showing that something can happen in the lab is different from saying that it did happen, he emphasizes. “This reaction only becomes truly important if we can show that there is some kind of selective advantage to the network of chemicals involved.” If that’s the case, it could begin to explain how nonliving chemistry generated reactions that eventually evolved into living systems. But discovering the exact sequence of events that gave life its spark may be forever lost behind time’s horizon, Hazen warns. “Like so many chemical experiments pitched as ‘origins of life’ contributions, [this] is more suggestive than definitive.”
By Robert F. Service |
A fundamental property of life is the ability to replicate itself. Researchers have now created the first molecules of RNA, DNA’s singled-stranded relative, that are capable of copying almost any other RNAs. The discovery bolsters the widely held view among researchers who study the origin of life that RNA likely preceded DNA as the central genetic storehouse of information in the earliest cells some 4 billion years ago. Ironically, the new RNA copiers still can’t duplicate themselves. But if future souped-up versions can pull that off, it could do more than reinforce notions of RNA’s primordial role—it could lead to the creation of the synthetic modern microbes that use RNA as their sole source of genetic information.
In order to grow and replicate, all modern cells require DNA, RNA, and proteins, and the synthesis of each inside cells requires the other two. Researchers in the 1960s hypothesized that modern cells evolved from progenitors that didn’t require this interdependence. RNA seemed a likely first biomolecule, because, like DNA, it can store information, and, like proteins, it can act as a catalyst to speed up certain chemical reactions. Researchers also discovered early on that RNA is at the core of several modern enzymes critical to life, such as the ribosome that builds proteins. So some scientists hypothesized life that started as an “RNA world”—a period in which RNA controlled both the genetics and biochemistry inside all cells.
If RNA were central to early biochemistry, RNAs must have been able to copy themselves in order for those cells to multiply and evolve. Finding such an RNA copier “is the bull’s-eye of the RNA world hypothesis,” says Gerald Joyce, a chemist at the Scripps Research Institute in San Diego, California. Modern cells instead have a protein-based enzyme called RNA polymerase (RNAP) that copies strands of DNA into their RNA equivalent. In 1993, researchers led by Jack Szostak at Harvard University created an all-RNA version of RNAP, also known as an RNAP ribozyme, which joined two small pieces of RNA on a separate template RNA strand. Since then, Szostak’s team and other have continued to improve their RNA copiers. Two years ago, for example, researchers in the United Kingdom reported isolating an RNAP ribozyme capable of stitching together RNAs up to 200 nucleotides long, again when matching them up to a template strand.
The problem with all of these RNAP ribozymes, Joyce notes, is that they are finicky. They can copy only certain sequences of nucleotide bases, the building blocks that make up RNA and DNA, and those sequences don’t carry out any important function inside cells. So Joyce and his postdoctoral assistant David Horning attempted to come up with a more versatile RNAP ribozyme, using a well-known technique known as in vitro evolution.
They started by synthesizing a large library of DNA strands intended to encode the starting RNAP ribozyme. But they randomly mutated the DNA sequence, ensuring each of the final RNAPs would be different. They added these RNAPs to a vial containing small RNA snippets they wanted to link together on another template RNA strand. If the RNAP ribozyme successfully created a new RNA, the new strand would signal that by binding to a specific molecular target in its vial. And because each RNAP ribozyme was engineered to remain tethered to its new, synthesized RNA strand, this allowed the team to isolate any successes. Each captured RNAP ribozyme was then used as the starting point for another round of evolution.
After 24 rounds of this test tube evolution, in which the scientists successively upped the requirements for what a RNAP ribozyme had to do to be successful, they wound up with one called 24-3 polymerase. That RNA strand, they report online today in the Proceedings of the National Academy of Sciences, is able to copy almost any other RNA, from small catalysts to long RNA based enzymes. The 24-3 polymerase was also able to make copies of RNAs it had already copied, allowing it to amplify the presence of particular RNAs 10,000-fold. That provided the first RNA version of the polymerase chain reaction, a widely used technique to make copies of DNA.
“This paper is an important breakthrough in an ongoing effort to complete the ‘RNA first’ model for the origin of life,” says Steven Benner, an origin-of-life chemist at the Foundation for Applied Molecular Evolution in Alachua, Florida. But Benner cautions that a true confirmation of the RNA world remains a ways off. Not only does 24-3 polymerase’s tightly wound structure prevent it from being able to copy itself, but Benner notes that it has taken the chemistry community 25 years to come up with an RNA copier proficient at copying other RNAs, despite all the tools of modern biochemistry. “[That] suggests we are still missing something important,” Benner says.
Joyce agrees and notes that even if an RNA world preceded the rise of DNA and proteins, it too may have been preceded by earlier forms of biochemistry. Nevertheless, Joyce adds, he and Horning are pressing on to improve 24-3 polymerase further in hopes of making a version that can copy itself. If they succeed, Joyce says, such a molecule could then become the basis for the first synthetic cells that use RNA as the sole genetic information molecule.
Robert F. Service
Jack Szostak knows he’ll never realize his ultimate scientific dream. But if he pulls off number two on his list, “it will go down in history as the greatest experimental achievement ever,” says John Sutherland, an organic chemist at the Medical Research Council’s Laboratory of Molecular Biology in Cambridge, U.K. Not bad for a backup.
Szostak, a molecular biologist at Harvard University and Massachusetts General Hospital in Boston, has already accomplished some spectacular science. He shared the 2009 Nobel Prize in physiology or medicine for helping to reveal the role of telomeres, the end bits of chromosomes that help protect genetic instructions during cell division. But more than a decade ago, Szostak shifted his lab’s focus to exploring how life on Earth may have gotten its start. He would dearly love to know the recipe for the primordial soup in which it all began some 4 billion years ago. That recipe is almost assuredly lost to history. “We don’t have a time machine,” Szostak says. “We can’t go back.”
So he hopes to do the next best thing: fiddle around with a few ingredients of his own and watch as they spontaneously assemble themselves into genes inside simplified cells that copy themselves and demonstrate the first emergent signs of Darwinian evolution. The origin of life. Again. Only this time in a lab.
A lab demonstration wouldn’t prove that life emerged the same way, Szostak says, but it would begin to tell a plausible story about how chemistry made the transition to biology. “If we can do that, to me it would give us a pretty good understanding of how life got started.”
It’s a big if. But on page 1098, Szostak and Katarzyna Adamala, his former graduate student and now a postdoctoral associate at the Massachusetts Institute of Technology in Cambridge, report taking a major step in that direction. For the first time, they found a recipe that promotes RNA copying inside primitive “protocells.” It’s not life in the lab—not yet—but other origin-of-life researchers are watching closely, says Gerald Joyce, a chemist and origin-of-life researcher at the Scripps Research Institute in San Diego, California. “You never want to bet against Jack,” Joyce says. “He has a really good nose for where to go.”
For an RNA-containing protocell to display Darwinian evolution, Szostak says eight large problems must be surmounted (see table, p. 1034). His lab has already solved three, and he says it is closing in on another three. That leaves two to go. “It’s tantalizing,” Szostak says. “We’re close.” And he’s not the only one who thinks so. “I’d be hugely surprised if we don’t get to that [during my career],” says Matthew Powner, a former postdoctoral assistant of Szostak’s who now runs his own lab at University College London. “There is tangible excitement that this can be solved and this will mean something big.”
In the beginning
In tackling the origin of life, Szostak is taking on one of the biggest questions humanity has ever asked—second only to the origin of the universe itself. For millennia, it lay in the realm of philosophy, theology, and alchemy. Science got in on the act in a systematic way in the mid-20th century, after researchers discovered the structures of DNA and RNA and their central role in coding for proteins, the chemical workhorses of the cell. In a host of now-classic experiments, scientists probed how potential building blocks of life such as amino acids and nucleic acids could be synthesized from simple compounds under conditions thought to have prevailed on early Earth. Progress was rapid and spirits high. “Laboratories will be creating a living cell within ten years,” Colin Pittendrigh, an American biologist, predicted in 1967.
Then things got complicated. Researchers realized that creating the raw ingredients of life wasn’t enough: They also needed to explain how those compounds assembled themselves and evolved into the sophisticated living cells on Earth today. Life required not just the right ingredients, but also the right molecular tools. In the late 1960s, a trio of biologists—Francis Crick, Carl Woese, and Leslie Orgel—independently proposed that RNA could serve two roles. What came to be known as the “RNA World” hypothesis holds that RNA existed long before DNA, catalyzed its own reproduction, and helped give life its start. Others believed RNA wasn’t up to the task and proposed alternatives for the earliest biochemistry, developing the “peptide world,” “lipid world,” and “metabolism first” scenarios for life’s origin. Conferences on the subject became shouting matches. “They all fought each other tooth and nail,” Sutherland says. “People wondered, ‘How on Earth do you solve this problem?'”
Throughout most of history, the answer had been simple: divine intervention. Szostak, though, takes pleasure in pushing back the borders of the supernatural. “To me it’s very satisfying to find natural explanations for problems that were so complex that people had to resort to magic,” he says. But he insists that he is not a philosopher; he simply likes to solve problems at the lab bench.
Szostak has had a practical bent for most of his life. The eldest child of an aeronautical engineer father and a mother who held down various jobs, he grew up in Ottawa and Montreal. As a child, his parents took him to church and Sunday school but weren’t particularly devout themselves. “When I was 12, I said I’m not going to do that anymore,” Szostak says; his parents seemed more relieved than anything else.
In his teens, Szostak became absorbed in chemistry. His mother was working as a librarian for a chemical company and used to bring home ingredients for his basement lab. His early experiments left “a few little scars,” Szostak says. But he chuckles, “I still have all my fingers.”
After earning an undergraduate degree at McGill University in Montreal in 1972, Szostak moved to Cornell University to work with biologist Ray Wu. Wu’s lab was racing to synthesize DNA fragments that could detect messenger RNA—the form of RNA that carries copies of genes to ribosomes, which translate their code into proteins. Wu’s lab lost out by a few months to British biologist Michael Smith. Szostak didn’t come in second often after that.
After setting up his own lab, Szostak plunged into the burgeoning field of genetics. He helped develop the yeast artificial chromosome, a technique that was widely used to identify, clone, and manipulate genes. He identified the specialized sequences of telomeres and helped show how they aid in cell division and how telomeres contribute to cell aging, hereditary diseases, and cancer.
Szostak’s success brought other researchers flocking to work with telomeres. “The field was getting crowded,” Szostak says. “I thought maybe it was time to do something different.” He drew inspiration from experiments by Thomas Cech of the University of Colorado, Boulder, and Sidney Altman of Yale University, for which they won their own Nobel in 1989. In the early 1980s, Cech and Altman found that RNA not only serves as a genetic mail carrier but can also catalyze chemical reactions. Because that role was previously thought to be the sole domain of proteins, the finding bolstered the RNA World hypothesis.
In the early 1990s, Szostak switched his lab’s focus to RNA catalysts, known as ribozymes. He and his colleagues invented a scheme for evolving new ribozymes in the lab, in a process known as in vitro selection. (Joyce’s group at Scripps carried out similar work.) In 1995, Szostak and former students Eric Ekland and David Bartel used the technique to produce the first RNA catalyst capable of welding two other pieces of RNA together. A year later, Ekland and Bartel announced that they had found an RNA catalyst capable of serving as an RNA polymerase, the enzyme that living cells use to produce new copies of an RNA strand.
RNA was proving increasingly versatile, with multiple roles previously reserved for DNA and proteins. In 2000, researchers at Yale discovered that even the catalytic heart of the ribosome is an RNA-based ribozyme. Here was a possible relic of the RNA World, strongly supporting the idea that early life ran on RNA and only later evolved the ability to build chemically superior proteins.
Szostak found himself thinking more and more about the RNA World. The hypothesis had its problems, he realized. “RNA brings with it a lot of baggage,” Szostak says. It is a fragile molecule, so researchers would need to explain how it could have survived conditions on early Earth. They would also need to explain how long RNA chains formed, were copied, split apart, and sent to daughter cells—the cycle of replication that is basic to life.
Most fundamentally, it wasn’t at all clear how an RNA fragment drifting around in a warm pond or stuck on a fleck of mineral could have spawned variants that would have reproduced more or less rapidly, allowing “fitter” variants to outcompete others. What allowed primordial RNA to evolve?
All of the above
After numerous conversations with other origin-of-life researchers, Szostak became convinced that RNA couldn’t have done it alone. The molecules needed to be isolated and confined. Some sort of cell membrane probably was needed, both to concentrate the ingredients of life and to promote a Darwinian process. “If [chemistry] is compartmentalized, you keep molecules related by descent together,” Szostak explains. If an RNA-containing protocell arises and can grow and divide better than its neighbors can, it can pass its advantages to its progeny. The protocells would allow fitter molecules to flourish, in true Darwinian fashion.
“I thought, ‘Well, I’ve never worked on membranes before,’ ” Szostak says. ” ‘Maybe it’s time to do so.’ ;” Protocell membranes, he knew, must have been very different from those of modern cells. Current cell membranes are made from fats called phospholipids and are all but impenetrable to key ingredients of life such as amino acids and nucleic acids. Without the modern biochemical apparatus of protein-based pores and pumps, nutrients cannot get in and waste products can’t get out.
Szostak and his students found an alternative. They discovered that far simpler fatty acid molecules could form leaky cell-like spheres that allowed ions, amino acids, and nucleic acids to diffuse in. In 2008, Szostak’s team reported that RNA nucleotides, or building blocks, could enter these cells and then form growing RNA chains that were too big to diffuse back out. A year later, Szostak and his graduate student Ting Zhu found that adding extra fatty acid molecules to the mix caused existing protocells to grow. Then, modest shear forces—such as those that protocells might experience when flowing through a column of warm water near a volcanic vent—would stress the large spheres until they divided, and any RNA inside them would be partitioned among the daughter cells. Yet another paper showed that RNA or peptide catalysts would speed the incorporation of additional fatty acid molecules into protocells, promoting their growth. Crude as they were, fatty acid vesicles appeared to be up to the job.
What about the other key component, RNA? Advances both in Szostak’s lab and elsewhere showed that, with the right mix of ingredients, individual RNA nucleotides would bind to a sister “template” strand in a copying process without the enzymes required inside modern cells. That was good news—but researchers couldn’t make it happen inside a protocell.
The biggest problem was that one of the most important ingredients for copying an RNA template without added enzymes is charged magnesium ions (Mg2+). Take away Mg2+ and the reaction proceeds so slowly, it’s hard to imagine how it could have been relevant to early life. But Mg2+ has downsides. The ions rip apart fatty acid protocells and shred growing RNA chains as fast as they build them up.
Adamala says she tried adding hundreds of different compounds and short peptides to the mix. “Nothing worked,” she says. “It was very frustrating.” But then she turned to metal-binding compounds called chelators, and one gave her the result she was looking for. In their current paper, Adamala and Szostak report that when they added a bit of a simple citric acid derivative called citrate to the mix, they got a perfect Goldilocks result. The citrate bound the Mg2+ ions tightly enough to keep the ions from tearing apart either the RNA or the fatty acid membranes, but loosely enough to give the Mg2+ ions leeway to copy a template RNA strand.
“It’s a beautiful paper,” Sutherland says. Citrate itself is a tantalizing solution, he says. It also plays a key metabolic role in modern cells, which suggests that it, too, could be a molecular fossil left over from early evolution.
Equally important, Sutherland says, is that for the first time, all the various pieces of the protolife puzzle seem to be coming together. “The big picture is it’s not an RNA world, a peptide world, a lipid world. It only works if everything is connected,” Sutherland says. George Cody, an organic geochemist at the Carnegie Institution for Science in Washington, D.C., agrees. “In the beginning, all these had to be in play,” he says.
Next, Szostak says, his team must overcome two large hurdles: The researchers must show how individual RNA bases could have become chemically “activated” so they would readily bind to growing RNA strands. Then they must demonstrate how RNA strands can duplicate without a starter template strand to help the nucleotides come together to form the complementary strand. Sutherland thinks these are solvable problems. “There’s no reason it shouldn’t be possible to recreate [a replicating cell],” he says.
Even if Szostak’s experiment works, there will still be plenty of unanswered questions. Among them: What prebiotic processes would have produced the RNA nucleotides and other mix of ingredients that would have gone into an early protocell? It’s also not clear that an evolving protocell made in the lab would have any broader significance, says Ramanarayanan Krishnamurthy, an organic chemist at Scripps. “Pushing its relevance to what happened 4 billion years ago is a risky thing.”
But Szostak argues that such dismissals are too facile. Such a “cell” would help define the chemistry that must have been involved at some level to get a self-replicating system going. Sutherland likens it to a crossword puzzle. As you begin to fill in words in some of the open squares, the options narrow for the words that intersect each known word. The puzzle shrinks, making subsequent answers easier. For someone aiming to show that the puzzle of life’s origin didn’t solve itself by magic, that would be a satisfying result indeed.
Thomas R. Cech
The amino acids we obtain by digestion of steak, salmon, or a lettuce salad are loaded onto transfer RNAs (tRNAs) and rebuilt into proteins in the ribosome, the cell’s macromolecular protein-synthesis factory. The bacterial ribosome is composed of three RNA molecules and more than 50 proteins. Its key components are so highly conserved among all of Earth’s species that a similar entity must have fueled protein synthesis in the common ancestor of all extant life. Although the chemical reaction catalyzed by the ribosome is simple—the joining of amino acids through amide (peptide) linkages—it performs the remarkable task of choosing the amino acids to be added to the growing polypeptide chain by reading successive messenger RNA (mRNA) codons. On page 905 of this issue, Steitz, Moore, and colleagues now provide the first atomic-resolution view of the larger of the two subunits of the ribosome. From this structure they deduce on page 920 that RNA components of the large subunit accomplish the key peptidyl transferase reaction. Thus, ribosomal RNA (rRNA) does not exist as a framework to organize catalytic proteins. Instead, the proteins are the structural units and they help to organize key ribozyme (catalytic RNA) elements, an idea long championed by Harry Noller, Carl Woese, and others.
These landmark publications are but the latest chapter in a progression of ribosome structural studies that have spanned four decades. Early electron micrographs of ribosomes in action led to immunoelectron microscopy and ultimately to cryo-electron microscopy images of about 20 Å resolution. Proteins were also located within the ribosome by neutron scattering. However, to achieve atomic resolution, x-ray crystallography is required, a daunting task given the huge size (2.6 × 106 daltons) and asymmetry of the ribosome. The pioneering crystallization of ribosomes from the bacterium Haloarcula marismortui in the 1980s by Ada Yonath and H. G. Wittmann provided the first rays of hope, but it is only in the past few years that crystal structures have been determined for the large subunit (5 Å resolution), the small subunit (5.5 Å resolution), and the whole ribosome complexed with tRNAs (7.8 Å resolution).
Now, at 2.4 Å, almost the entire chain of the 23S rRNA and its tiny 5S rRNA partner, totaling 3043 nucleotides, have been fitted into the electron density map of the H. marismortui large ribosomal subunit. The RNA secondary structure (intramolecular base-pairing pattern) of the large-subunit rRNA had been determined previously, and is present as predicted in the x-ray structure. In addition, a large number of unpredicted RNA tertiary structure interactions are now seen. Overall, the RNA forms a huge single mass of tightly packed helices, not six discrete domains connected by floppy linkers as a naïve observer might predict from looking at the secondary structure diagram.
Where, then, are all of the proteins, and what is their function? The globular domains of 26 proteins are found largely on the exterior of the subunit. Twelve of these proteins have unusual snake-like extensions, devoid of tertiary structure and in some cases even secondary structure, and an additional protein is entirely extended; their shapes are molded by their interactions with the RNA. From these pictures, and from what is known about protein cofactors that facilitate the action of some other ribozymes, it is likely that these ribosomal proteins buttress, stabilize, and orient the otherwise floppy RNA into a specific, active structure.
The part of the subunit’s surface that is most devoid of protein is the active-site region. This was precisely located by soaking the crystals in a small-molecule inhibitor provided by Michael Yarus. This inhibitor is an analog of the anionic tetrahedral intermediate formed when a nucleophile attacks a planar carbonyl. (In protein synthesis, the nucleophile is the amino group of the amino acid in the ribosome’s A-site, and the carbonyl belongs to the P-site amino acid esterified to the 3′-ribose of tRNA.) It is the absence of any protein moiety within 18 Å of the correctly bound inhibitor in their structure, coupled with earlier work that defined this conserved part of the large-subunit rRNA as the “peptide transferase center,” that led the authors to conclude that RNA (and not protein) must be responsible for catalysis. The ribosome is a ribozyme, admittedly one dependent on structural support from protein components—substantially deproteinized large subunits still carry out peptidyl transfer, although complete deproteinization destroys this reactivity.
The authors propose a detailed mechanism for catalysis that will undoubtedly be the subject of much analysis and experimental testing. One key feature of the mechanism is a particular adenine base (conserved at this position in thousands of sequenced rRNAs) that acts as a general acid-base catalyst, deprotonating the nucleophilic amine and protonating the 3′-oxygen of the ribose reaction product. The ability of RNA to provide general acid-base catalysis was discovered only last year in studies involving the hepatitis delta virus ribozyme.
Efficient general acid-base catalysis requires that the acid-base have a pKa around pH 7.0, whereas the adenine base titrates at or below pH 3.5. However, it is already known that certain RNA structures can perturb the pKa of adenine toward a neutral pH. In addition, as Muth et al. report on page 947 of this issue, experimental analysis of the nucleotides within the peptidyl transferase center demonstrates that the adenine implicated by the crystal structure has an unusual pKa of 7.6. Remarkably, two RNAs—identified by in vitro evolution for their ability to catalyze peptidyl transfer or to bind the analog of the reaction intermediate —have adenines in a local sequence and secondary structure similar to that of the critical adenine in the ribosome. So, this pair of RNAs may recapitulate the key feature of the rRNA reaction mechanism.
Of course, general acid-base catalysis can easily be provided in the active site of a protein enzyme, which leads to the question: Why does nature use RNA catalysis to achieve protein synthesis? One argument is evolutionary. If, indeed, there was an early RNA world where RNA provided both genetic information and catalytic function, then the earliest protein synthesis would have had to be catalyzed by RNA. Later, the RNA-only ribosome/ribozyme may have been embellished with additional proteins; yet, its heart of RNA functioned sufficiently well that it was never replaced by a protein catalyst. But there are persuasive chemical arguments as well. The substrates of the ribosome are RNAs—aminoacylated tRNAs and an mRNA—and RNA is particularly well suited for specific recognition of other RNAs through formation of base pairs, base triples, and other interactions. Furthermore, RNA is well suited to perform very large-scale conformational changes, and such movements are required for protein synthesis.
These most recent contributions of Steitz, Moore, and colleagues provide a milestone, but not the finish line. This one structure contains more RNA-RNA and RNA-protein interactions than all previous atomic-level structures combined, so ribophiles can look forward to years of additional analysis. The whole ribosome needs to be brought to this same atomic level of resolution, and the proposed reaction mechanism deserves critical testing. Finally, the molecular basis of the mRNA translocation step that must occur after each peptidyl transfer event remains obscure. Thus, although the current crystal structure provides one beautiful frame, we still look forward to seeing the entire movie.
Carbonaceous asteroids represent the principal source of water in the inner Solar System and might correspond to the main contributors for the delivery of water to Earth. Hydrogen isotopes in water-bearing primitive meteorites, e.g. carbonaceous chondrites, constitute a unique tool for deciphering the sources of water reservoirs at the time of asteroid formation. However, fine-scale isotopic measurements are required to unravel the effects of parent body processes on the pre-accretion isotopic distributions. Here we report in situ micrometer-scale analyses of hydrogen isotopes in six CM-type carbonaceous chondrites revealing a dominant deuterium-poor water component (δD = -350 ± 40 permil) mixed with deuterium-rich organic matter. We suggest that this D-poor water corresponds to a ubiquitous water reservoir in the inner protoplanetary disk. A deuterium-rich water signature has been preserved in the least altered part of the Paris chondrite (δDParis > -69 ± 163 permil) in hydrated phases possibly present in the CM rock before alteration. The presence of the D-enriched water signature in Paris might indicate that transfers of ice from the outer to the inner Solar System have been significant within the first million years of the Solar System history.
Observed hyperbolic minor bodies might have an interstellar origin, but they can be natives of the Solar system as well. Fly-bys with the known planets or the Sun may result in the hyperbolic ejection of an originally bound minor body; in addition, members of the Oort cloud could be forced to follow inbound hyperbolic paths as a result of secular perturbations induced by the Galactic disc or, less frequently, due to impulsive interactions with passing stars. These four processes must leave distinctive signatures in the distribution of radiants of observed hyperbolic objects, both in terms of coordinates and velocity. Here, we perform a systematic numerical exploration of the past orbital evolution of known hyperbolic minor bodies using a full N-body approach and statistical analyses to study their radiants. Our results confirm the theoretical expectations that strong anisotropies are present in the data. We also identify a statistically significant overdensity of high-speed radiants towards the constellation of Gemini that could be due to the closest and most recent known fly-by of a star to the Solar system, that of the so-called Scholz’s star. In addition to and besides 1I/2017 U1 (`Oumuamua), we single out eight candidate interstellar comets based on their radiants’ velocities.