Volcanic origin of proteins? - The Scientist - Magazine of the Life Sciences

Volcanic origin of proteins? - The Scientist - Magazine of the Life Sciences

Volcanic origin of proteins? The reanalysis of a 1958 experiment suggests that volcanic eruptions may have spawned the amino acids that contributed to the rise of life on earth [Published 21st March 2011 08:00 PM GMT]

Scientific debates don't get much hotter than the one surrounding the origin of organic molecules at the dawn of life on Earth. New findings, based on a reanalysis of a 50-year-old experiment, suggests that ancient volcanic activity was the source of the very first amino acids. The findings, published open access today (March 21) in the Proceedings of the National Academy of Sciences, lend support to the theory that the building blocks of organic life spewed from volcanoes billions of years ago. "Volcanic discharges could have been important in forming pre-organic molecules, which is consistent with this experiment," said volcanologist Clive Oppenheimer of the University of Cambridge, who was not involved with the study. "And it's a nice piece of science revisiting itself." Lightning struck during the eruption of Mount Rinjani in Indonesia in 1995 Image: Wikimedia Commons, Oliver Spalt In the 1950s, Stanley Miller and Harold Urey of the University of Chicago performed a series of "spark discharge" experiments, in which the researchers applied electrical sparks-- meant to simulate lightning -- to a mixture of gases in steam-filled flasks. As the heat inside the flasks rose and the sparks flew, solids were produced and were captured in vials that could be stored for later analysis. Amino acids were formed in these reactions and they provided support for Miller's hypothesis that organic molecules could be formed from inorganic gases. When Miller died in 2007, he left his entire lab to his second graduate student Jeffrey Bada, who is now a marine chemist at the Scripps Institution of Oceanography. Among this collection was a small cardboard box with the words "spark discharge" scrawled on its side. Inside the box were some of those vials from the 1950s experiments containing solid product, some of it unanalyzed. "It's like someone had hit me over the head with a bat," said Bada of the find. "I was just flabbergasted that he had never mentioned it." Out of this collection, Bada selected two vials for analysis: one, the result of Miller's original 1953 experiment, which Bada analyzed for a 2008 publication, and a second, the first of few experiments Miller performed using sulfur gas. In this experiment, conducted in 1958, Miller mixed hydrogen sulfide with carbon dioxide, ammonia and methane -- a combination that Bada recognized as representing the gaseous makeup of a volcanic plume, in which reducing gases from the volcano interact with neutral or oxidizing atmospheric gases. "Volcanism was probably more prevalent in early earth," said Oppenheimer. "There was a hotter mantle, and the planet's bombardment by meteorites in itself generates a lot of volcanism." The experiment's combination of gases is also similar to the chemical mixture issuing from hydrothermal vents and analyzing the results could lend support to the hypothesis that both volcanoes and vents are the cradles of life. When Bada and his colleagues analyzed the product from Miller's 1958 vial, they found 23 different amino acids -- more than had ever before been produced from inorganic components -- a quarter of which contained sulfur from the simulated volcanic plume. "One of the most striking things you get out of that experiment is that hydrogen sulfide enriches the abundance and diversity of amino acids" compared to experiments that don't contain sulfur, Bada said. But the composition of the early atmosphere is a controversial subject, and not everyone is convinced that the conditions of the 50-year old experiment are representative of young Earth. Most of the evidence for early atmospheric composition is fossil based -- identifying the oxidation state of minerals, for example, or looking at fossil soils -- with no direct samples, so "most of the inferences are made indirectly," said Oppenheimer. Astrobiologist David Grinspoon of the Denver Museum of Nature and Science describes the opposing ideas about the early atmosphere and why these experiments are still meaningful. Miller's spark apparatus he designed with Urey in teh 1950's. Image: Wikimedia Commons "It's almost impossible that the early atmosphere looked like that," said planetary scientist Jim Kasting of Pennsylvania State University, who did not participate in the research. Plus, he argued, over the past 20 years, many scientists have begun to argue that RNA molecules, not amino acids, were the organic molecules that generated Earth's first life. "None of those ideas make these experiments irrelevant," countered David Grinspoon, the curator of astrobiology at the Denver Museum of Nature and Science, who was not involved with the study. "It's still a very interesting set of experiments to inquire about the chemistry produced in the local environments of sulfur-rich volcanoes on the early Earth." In addition to yielding clues about the origin of life on Earth, the old experiment may hold implications for the existence of life elsewhere in the universe, the authors argue. The relative abundances of the amino acids generated in the experiment were strikingly similar to those found on carbonaceous chondrite meteorites. These primitive and unaltered meteorites are thought to represent the basic material and chemistry in the universe. "Something about the way these things were produced in the experimental apparatus mimics the way amino acids were produced in these meteorites," said Grinspoon. "It implies a universality to those chemical pathways that is very relevant to thinking about life elsewhere in the universe." E.T. Parker et al., "Primordial synthesis of amines and amino acids in a 1958 Miller H2S-rich spark discharge experiment," Proceedings of the National Academy of Sciences, 2011, DOI: 10.1073/pnas.1019191108 Related stories: Astrobiology Isn't a Dirty Word Anymore [19th January 2004] Scientists Debate RNA's Role At Beginning Of Life On Earth [31st March 1997] Related F1000 Evaluations: Synthesis of activated pyrimidine ribonucleotides in prebiotically plausible conditions M. Powner et al., Nature, 459(7244):239-42, 2009. Evaluated by Sabine Muller, Ernst-Moritz-Arndt-Universitat Greifswald -- Donald Burke, University of Missouri School of Medicine -- Laura Landweber, Princeton University -- Niles Lehman, Portland State University -- Fritz Eckstein, Max Planck Institute -- Peter Unrau, Simon Fraser University.

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Fungus fights malaria? - The Scientist - Magazine of the Life Sciences

Fungus fights malaria? - The Scientist - Magazine of the Life Sciences

A Promiscuous DNA Packaging Machine from Bacteriophage T4

Complex viruses are assembled from simple protein subunits by sequential and irreversible assembly. During genome packaging in bacteriophages, a powerful molecular motor assembles at the special portal vertex of an empty prohead to initiate packaging. The capsid expands after about 10%–25% of the genome is packaged. When the head is full, the motor cuts the concatemeric DNA and dissociates from the head. Conformational changes, particularly in the portal, are thought to drive these sequential transitions. We found that the phage T4 packaging machine is highly promiscuous, translocating DNA into finished phage heads as well as into proheads. Optical tweezers experiments show that single motors can force exogenous DNA into phage heads at the same rate as into proheads. Single molecule fluorescence measurements demonstrate that phage heads undergo repeated initiations, packaging multiple DNA molecules into the same head. These results suggest that the phage DNA packaging machine has unusual conformational plasticity, powering DNA into an apparently passive capsid receptacle, including the highly stable virus shell, until it is full. These features probably led to the evolution of viral genomes that fit capsid volume, a strikingly common phenomenon in double-stranded DNA viruses, and will potentially allow design of a novel class of nanocapsid delivery vehicles.

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Nature (nº especial)The Human Genome at Ten .

The Human Genome at Ten

The draft human genome sequence was published on February 15 2001. Its publication promised great insights into human biology, medicine and evolution; it also changed the way life science research was done. In this special, Nature reflects on the past ten years to take stock of what we have learnt about the genome itself and about us - our biology, evolution and the genetic basis of human disease. From today's standpoint we also look into the future of human genomics, with a special focus on its role in clinical medicine.

Jaime Pellicer y el mayor genoma secuenciado

Jaume and the Giant Genome

Japanese canopy plant (Paris japonica)

He found that the canopy plant genome had 150 billion base pairs—50 times as many as human DNA. If the DNA in a human cell were unraveled, it would stretch to two meters. A strand of DNA in the canopy plant would span 100 meters. 

In fact, in humans, only about 1.5 percent of the genome’s DNA codes for proteins. In the Japanese canopy plant the percentage is sure to be even less. The function of that surplus DNA—or even whether there is a function—is a hotly debated mystery and will likely remain so until the species is sequenced. 

Noncoding sequences used to go by the derogatory names “selfish” or “junk” DNA, but have more recently acquired milder tags, including “transposable elements” or “jumping genes.” Unless somehow restrained, these proliferate across genomes like weeds. One sequence, called Alu, has copied itself a million times and makes up some 10 percent of the human genome.

There is, however, some evidence that the canopy plant, despite—or perhaps because of—its huge genome, maintains a competitive edge over plants that share its mountain habitat. In the chilly months of early spring, while neighboring competitors sit dormant, and before overhead trees come into leaf, the plant gets a jump-start on growth by pumping its cells full of water. This cellular expansion allows the canopy plant to increase its size and soak up more sunlight before DNA replication and cell division occur in the warmer summer months.


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Agricultura primitiva en microorganismos

The social amoeba Dictyostelium discoideum is well known for its social interactions. When prey bacteria become scarce, amoebae aggregate by the tens of thousands and produce a multicellular migratory slug that becomes a fruiting body in which about 20% of cells die to form a sterile stalk. The stalk aids the dispersal of the remaining cells, which differentiate into spores in a spherical structure called the sorus.  We show that about one-third of wild-collected clones husband bacteria through the sporulation and dispersal process. We call these clones farmers because they carry, seed and prudently harvest their food, but the farming is primitive because no active cultivation is known.

Leer mas

By L. Caetano M. Antunes, Julian E. Davies and B. Brett Finlay

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Mining Bacterial Small Molecules

As much as rainforests or deep-sea vents, the human gut holds rich stores of microbial chemicals that should be mined for their pharmacological potential.

animate4.com ltd. / Photo Researchers, Inc.

Companies spend huge resources going to the far reaches of the Earth to search for the next blockbuster. But we need look no further than our own intestines, which are populated with thousands of bacterial species that are constantly producing and releasing small, bioactive molecules.
Small molecules—the bread and butter of pharmaceutical companies—are compounds of low molecular weight (under 3,000 daltons) and diverse chemical composition. Examples of such molecules are the steroid and small-peptide hormones of higher organisms, with a molecular weight around 300 daltons, which have many important biological functions. The term hormone (from the Greek: excite, arouse) was coined in 1905 by British physiologist¹ Ernest Starling to describe the chemical messengers produced in an organ or gland of the body that travel to distant organs to exert their physiological effects. In humans, the critical functions of small-molecule hormones include modulation of the immune system, the development of sexual characteristics, the response to stress, metabolism, and mineral balance, among others.

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The Microbial Health Factor

Although much of our knowledge about bioactive small molecules comes from the study of mammalian and plant hormones, it is now known that bacteria can also produce, sense, and respond to a variety of small-molecule signals that enable them to act coordinately. Through the research of Alexander Tomasz on the acquisition and incorporation of foreign DNA by Streptococcus pneumoniae and Woodland Hastings’ studies of Vibrio fischeri luminescence, science had its first hints that diffusible molecules played an important role in the lifestyle of microbes.^2,3 Decades of subsequent research revealed that these hormone-like compounds are produced by these bacteria at basal levels and accumulate as their numbers increase. Both Tomasz’s and Hastings’ groups noticed that after reaching a threshold concentration, these molecules could regulate the incorporation of exogenous DNA and the production of light, activities that are only useful when undertaken by a population. (Bacteria can take up DNA individually, but when it is taken up by a group, the community can increase its chances of survival due to its greater genetic diversity.) Although the consequences of such discoveries were not fully appreciated at the time—it was unclear whether this behavior would be found in all bacteria—the observations formed the foundation for studies of bacterial communication. It is now widely accepted that many bacterial species use small chemical compounds to communicate with others of the same species, other bacterial species, and their hosts. Because this phenomenon is dependent upon a threshold cell density, bacterial communication has been termed “quorum sensing.”⁴

Intestinal molecular signaling
Microbes, both good and bad, can exert direct effects on host cells and vice versa. For example, pathogenic bacteria such as some strains of E. coli and Salmonella reduce the overall number of normal gut commensal bacteria, promoting their own growth, whereas some commensals have been shown to prevent pathogens from producing deadly Shiga toxin (A). Commensals also have essential chemical exchanges with the host. Gut bacteria are required for the normal development of the immune system, and the host actively dampens its normal immune response to allow commensals to grow (B). Pathogenic bacteria also affect the host cells directly, releasing signals that compromise the host immunity; indeed, some host signals, such as stress hormones, can exacerbate disease by increasing bacterial virulence (C). Because of their specific actions, these channels of chemical communication can be a valuable reservoir to tap for potential drugs. Like hormones, some these molecules could have downstream effects on distant organs like the pancreas, the lungs, or the brain. These channels of chemical communication can be a valuable reservoir to tap for potential drugs.

KEVIN HAND; Source: adapted from Physiol Rev, 90:859:904, 2010

The chemical repertoire used by bacteria to communicate is diverse, and new bioactive molecules continue to be discovered. Nonetheless, our knowledge of these molecules is limited. Studies of bacterial signaling have focused mostly on laboratory-grown, pure cultures of microorganisms. In the natural environment and in their hosts, microbes live in association with a multitude of other species and are constantly presented with opportunities for competition and cooperation.
One of the best-known natural examples is the nitrogen-fixation–driven symbiosis between Rhizobia and their legume hosts. Many chemical signals act to promote the establishment of this mutually beneficial relationship. For example, the growing root exudes flavonoids, which induce the surrounding Rhizobia to migrate to the root surface. There, quorum sensing occurs through the production of acyl-homoserine lactones, culminating in the production of microbial nodulation factors that act on the root and finally result in an endosymbiotic relationship. Although there is a wealth of information about chemical signaling in soil, many other complex microbial populations exist in nature, and it is certain that microbial signaling plays important roles in these communities.
At elevated concentrations, microbial signals can act as antimicrobials. In general, however, microbes produce antibiotics in the environment at concentrations that do not affect their growth.⁵ It is probable, then, that the main function of these chemicals is to modulate bacterial gene expression rather than to poison.⁶ Nevertheless, the study of chemicals derived from microbes and other organisms has provided us with more than just information about the roles that small molecules play in biological systems. Whenever possible, humans have taken advantage of these natural products for therapeutic purposes, the classic example being the fortuitous discovery of the antibiotic penicillin. In addition to antibiotics, natural products have been used as anticancer and anti-inflammatory compounds.^7,8 Many have been isolated from microorganisms, but others have been derived from plants and marine life. The discovery that the human body is made up of extremely complex ecosystems suggests that it, too, could be used as a rich source of new bioactive molecules.

The wealth within

At birth, humans are colonized by complex communities of microbes. These communities, which are established within the first year of life, have been termed microbiota, microflora or microbiome. The human microbiome is extremely rich, containing upwards of 10¹⁴ cells,⁹ and is essential to our health. Microbes colonize our skin, our gastrointestinal (GI), genitourinary, and respiratory tracts. Researchers have estimated that the collection of microbial genes in our bodies exceeds our own genes by a factor of 100, which means that the human genome is predominantly prokaryotic.

It is probable, then, that the main function of these chemicals is to modulate bacterial gene expression rather than to poison

Although virtually every body surface that is exposed to the environment harbors microbes, the gastrointestinal tract is by far the most heavily colonized site. More than 1,100 bacterial species have been genetically identified in the human gut; each individual carries an estimated 160 distinct species, only about one-tenth of which appear to be shared by everyone.^9,10 This offers a tremendous opportunity for the evolution of multiple microbe-microbe and host-microbe interactions, many of which are conveyed through the activity of small signaling molecules.
It has been known for a while that commensal organisms can use diffusible signals to interact with their hosts. Bacteroides thetaiotaomicron, a prominent member of the human gastrointestinal microbiota, produces signals that can control host gene expression. By doing so, the bacterium controls the availability of nutrients in its surroundings to favor its growth. More recently, this intestinal commensal has also been shown to communicate with pathogens by producing a yet to be identified signal that can control virulence-factor production by enterohemorrhagic Escherichia coli, a pathogenic strain of E. coli that can cause serious illness and death in humans. Colonization by B. thetaiotaomicron, and possibly by other bacterial species, may be an important tool used by mammals to control infection by virulent bacteria.
These interactions are not always initiated by the microbiota. Host-produced small molecules can also have profound effects on both commensals and pathogens. The mammalian stress hormones epinephrine and norepinephrine have been shown to affect commensal microbial populations in the gastrointestinal tract. Although the mechanism involved is not known, these hormones can favor the growth of specific species of the human microbiome. In addition to their roles in normal physiology, these mammalian stress hormones can also influence the production of virulence factors by invading pathogens. For instance, upon sensing intestinal epinephrine and norepinephrine, enterohemorrhagic E. coli activates the production of its type III secretion system, a major virulence factor. Also, Campylobacter jejuni, which commonly causes food poisoning, can respond to norepinephrine by improving its ability to enter host cells.

An even more daring possibility is that some of these molecules could be used to manipulate the physiology of remote organs and systems.

Although data on the importance of the human microbiome to health has been accumulating over the past few years, new evidence suggests that its contributions are not always local. The microbiota exerts an impact on host tissues and organs far away from the gut. Changes in intestinal commensal populations have been correlated with many diseases of remote organs, such as diabetes, asthma, obesity, cancer, autism, and even depression.⁹ The fact that these organs are not in direct contact with gut commensals suggests that chemical signals may be involved. For instance, it has been known for a while that antibiotic usage is correlated with an increased risk of allergic diseases, and it has been suggested that this is due to effects on the intestinal microbiota. Although microbial interactions with the human immune system are crucial in producing these pathologies, it is also possible that the intestinal microbiota affect systemic metabolites by a more general mechanism. Indeed, William Wikoff of the Scripps Research Institute and colleagues have recently shown that intestinal microbes can have a significant impact on mammalian blood metabolites, particularly those involved in amino acid metabolism, suggesting that the influence of gut microbes on the human body may be largely dependent on the activities of small molecules.¹⁰ Although some of these effects may be brought about directly by microbial signals, other mechanisms that propagate messages initiated by gut bacteria may also be at play.
The mammalian gut plays an important role in the excretion of waste, and many host-produced small-molecule metabolites that circulate in the gut are a result of this waste-production process. The GI tract is also loaded with other small molecules, such as hormones and bile acids, that not only have significant impact on the GI tract itself but also on other organs through reabsorption. In other words, the molecules with potential bioactivity may not necessarily come only from the microbiota, but also from our own waste products.
Some of these small molecules originating from the host and from the microbes are also likely to have important functions in keeping the relationship between hosts and their commensals in balance. Since these molecules have important functions in human health and disease, they could be mined as therapeutics aimed at maintaining or reestablishing homeostasis and preventing or curing diseases. Not least, the gut may be a source of new antibiotics. It is known that the microbiota exerts important effects on the maturation of the mammalian immune system, and the small molecules in the intestine could be used to modulate these relationships in controlled ways. An even more daring possibility is that some of these molecules could be used to manipulate the physiology of remote organs and systems. It is possible that the molecules produced by some of the microbes associated with protection against certain diseases could be used to remediate or prevent those illnesses. While the potential for applications is enticing, careful studies must be designed and performed to demonstrate that changes in bacterial populations and the molecules they produce during disease are in fact causing the pathological process rather than changing in response to it.

Stalling between discovery and drug development

One of the limitations of this potential source of bioactive small molecules is that, like bacteria isolated from deep-sea vents and other exotic locales, the majority of the microbial species present in the mammalian gut still cannot be cultured in the laboratory. Working out a bacterium’s ideal growth requirements is no simple matter. This has forced the use of culture-independent methods to study microbial communities in and on humans.
Most studies rely on metagenomics, or the unbiased sequencing of DNA fragments isolated from mixed microbial populations. This is useful from a phylogenetic standpoint because it allows us to determine the exact microbial composition of a given sample, but it tells us very little about functions of the compounds produced or the interactions between them. Based on analysis of the gut metagenome—the combination of all genes present in the GI tract—we can predict that many biological reactions are yet to be discovered. More recently, the intestinal environment has been studied using other culture-independent methods such as metatranscriptomics and metaproteomics, which focus on the unbiased analysis of messenger RNA or proteins, respectively. Altogether, these explorations of the microbial diversity in the GI tract suggest that significant phylogenetic diversity remains to be explored. These studies have provided much information about the composition of microbial communities in the mammalian gut, but it is only recently that we have begun to decipher the molecular functions of these assemblages.
With the overwhelming amount of genetic material present in the human gut comes the potential for an immensurable source of bioactive small molecules. As a result of recent advances in techniques of chemical separation and structural elucidation, particularly methods for high-throughput analysis of complex samples, we now have tools to probe this chemical lexicon. One such technique is Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FTICR-MS), which has recently been used in pioneering high-throughput studies of the mammalian metabolome.¹¹ FTICR-MS is an extremely sensitive and accurate method for the rapid detection and relative quantification of thousands of small molecules in complex samples. We have used FTICR-MS to study the intestinal metabolome and find that thousands of small molecules are present in the mammalian gut. Interestingly, the levels of the majority of these molecules are affected by antibiotic treatment, suggesting that the intestinal microbiota modulates the chemical composition of the intestinal lumen (Antunes and Finlay, submitted for publication). Additional metabolic studies of samples from healthy and disturbed ecosystems will allow predictions of causative associations between chemical variations and specific disease states.
But even these “-omic” studies, informative as they may be, will need to be verified and tested in basic laboratory experiments to tease apart the specific host-microbe interactions. There is a huge distance between beholding the vast landscape of molecules with potential human applications and finding potential disease interventions. The results from survey studies will need to be used to develop hypotheses that can then be tested using single molecules (natural or synthetic) to treat conditions in animal models, giving us insight not only into the healthy state, but also into how it can be maintained or restored during disease.
That DNA, RNA, and proteins are central to life is irrefutable. However, the functioning of living organisms not only depends on these molecules but, in most cases, extends to incorporate the end products of multiple metabolic pathways. In other words, in most cases it is the small molecules that are the crux of biological function. While other sources of bioactive molecules should not be ignored, harnessing the bacterial chemicals in our own gut may yield molecules that have already been shaped for very specific interactions through years of coevolution between humans and their microbial partners. Without identifying and studying these molecules, we will not fully understand the functions of metabolic pathways and the interconnections among them. Nor will we be able to fully comprehend the complexities of any biological system. The study of small molecules should be undertaken not only with an intellectual view toward understanding the molecular intricacies of life in more detail, but also with a practical view of benefiting from what these molecules may have to offer.
L. Caetano M. Antunes, F1000 Head of Faculty Julian E. Davies, and Section Head B. Brett Finlay are at the University of British Columbia, Vancouver, BC, Canada.

References:

1. E.H. Starling, “The chemical correlation of the functions of the body. Lecture I,” The Lancet, 2:339-41, 1905.

2. K.H. Nealson et al., “Cellular control of the synthesis and activity of the bacterial luminescent system,” J Bacteriol, 104:313-22, 1970.

3. A. Tomasz, “Control of the competent state in Pneumococcus by a hormone-like cell product: an example for a new type of regulatory mechanism in bacteria,” Nature, 208:155-59, 1965.

4. W.C. Fuqua et al., “Quorum sensing in bacteria: the LuxR-LuxI family of cell density-responsive transcriptional regulators,” J Bacteriol, 176:269-75, 1994.

5. E.B. Goh et al., “Transcriptional modulation of bacterial gene expression by subinhibitory concentrations of antibiotics,” PNAS, 99:17025-30, 2002. Free F1000 Evaluation

6. J. Davies, “Are antibiotics naturally antibiotics?” J Ind Microbiol Biotechnol, 33:496-99, 2006.

7. K.H. Lee, “Discovery and development of natural product-derived chemotherapeutic agents based on a medicinal chemistry approach,” J Nat Prod, 73:500-16, 2010.

8. O. Werz, “Inhibition of 5-lipoxygenase product synthesis by natural compounds of plant origin,” Planta Med, 73:1331-57, 2007.

9. I. Sekirov et al., “Gut microbiota in health and disease,” Physiol Rev, 90:859-904, 2010.

10. A. Vacharaksa, B.B.Finlay, “Gut microbiota: metagenomics to study complex ecology,” Curr Biol, 20:R569-71, 2010.

11. W.R. Wikoff et al., “Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites,” PNAS, 106:3698-703, 2009. F1000 ID 1157492, Free F1000 Evaluation

12. J. Han et al., “Towards high-throughput metabolomics using ultrahigh-field Fourier transform ion cyclotron resonance mass spectrometry,” Metabolomics, 4:128-40, 2008.

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