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  • richardmitnick 5:55 pm on December 10, 2014 Permalink | Reply
    Tags: , , Genetics, ,   

    From isgtw: “Supercomputer compares modern and ancient DNA” 

    international science grid this week

    December 10, 2014
    Jorge Salazar, Texas Advanced Computing Center

    What if you researched your family’s genealogy, and a mysterious stranger turned out to be an ancestor? A team of scientists who peered back into Europe’s murky prehistoric past thousands of years ago had the same surprise. With sophisticated genetic tools, supercomputing simulations and modeling, they traced the origins of modern Europeans to three distinct populations.The international research team’s results are published in the journal Nature.

    The Stuttgart skull, from a 7,000-year-old skeleton found in Germany among artifacts from the first widespread farming culture of central Europe. Right: Blue eyes and dark skin – how the European hunter-gatherer appeared 7,000 years ago. Artist depiction based on La Braña 1, whose remains were recovered at La Braña-Arintero site in León, Spain. Images courtesy Consejo Superior de Investigaciones Cientificas.

    “Europeans seem to be a mixture of three different ancestral populations,” says study co-author Joshua Schraiber, a National Science Foundation postdoctoral fellow at the University of Washington, in Seattle, US. Schraiber says the results surprised him because the prevailing view among scientists held that only two distinct groups mixed between 7,000 and 8,000 years ago in Europe, as humans first started to adopt agriculture.

    Scientists have only a handful of ancient remains well preserved enough for genome sequencing. An 8,000-year-old skull discovered in Loschbour, Luxembourg provided DNA evidence for the study. The remains were found at the caves of Loschbour, La Braña, Stuttgart, a ritual site at Motala, and at Mal’ta.

    The third mystery group that emerged from the data is ancient northern Eurasians. “People from the Siberia area is how I conceptualize it,” says Schraiber. “We don’t know too much anthropologically about who these people are. But the genetic evidence is relatively strong because we do have ancient DNA from an individual that’s very closely related to that population, too.”

    The individual is a three-year-old boy whose remains were found near Lake Baikal in Siberia at the Mal’ta site. Scientists determined his arm bone to be 24,000 years old. They then sequence his genome, making it the second oldest modern human sequenced. Interestingly enough, in late 2013 scientists used the Mal’ta genome to find that about one-third of Native American ancestry originated through gene flow from these ancient North Eurasians.

    The researchers took the genomes from these ancient humans and compared them to those from 2,345 modern-day Europeans. “I used the POPRES data set, which had been used before to ask similar questions just looking at modern Europeans,” Schraiber says. “Then I used software called Beagle, which was written by Brian Browning and Sharon Browning at the University of Washington, which computationally detects these regions of identity by descent.”

    The National Science Foundation’s XSEDE (Extreme Science and Engineering Discovery Environment) and Stampede supercomputer at the Texas Advanced Computing Center provided computational resources used in the study. The research was funded in part by the National Cancer Institute of the National Institutes of Health.

    See the full article here.

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  • richardmitnick 8:18 pm on December 8, 2014 Permalink | Reply
    Tags: , Genetics,   

    From UC Berkeley: “New therapy holds promise for restoring vision” 

    UC Berkeley

    UC Berkeley

    December 8, 2014
    Robert Sanders

    A new genetic therapy not only helped blind mice regain enough light sensitivity to distinguish flashing from non-flashing lights, but also restored light response to the retinas of dogs, setting the stage for future clinical trials of the therapy in humans.

    In normal mice with working photoreceptors (PR driven), stimulating the retina produces a variety of responses in retinal ganglion cells, the output of the eye. This can be seen in the colorful lower square, where measurements of the activity of different retinal ganglion cells are shown in response to the same stimulation. Photoswitches inserted into retinal ganglion cells (RGC) of blind mice produce much less variety of response (all evenly red means the cells fire at the same time), while blind mice with photoswitches inserted into bipolar cells (ON-BC driven) exhibit much more variety in their retinal response to light, closer to that of normal mice.

    The therapy employs a virus to insert a gene for a common ion channel into normally blind cells of the retina that survive after the light-responsive rod and cone photoreceptor cells die as a result of diseases such as retinitis pigmentosa. Photoswitches – chemicals that change shape when hit with light – are then attached to the ion channels to make them open in response to light, activating the retinal cells and restoring light sensitivity.

    Afflicting people of all ages, retinitis pigmentosa causes a gradual loss of vision, akin to losing pixels in a digital camera. Sight is lost from the periphery to the center, usually leaving people with the inability to navigate their surroundings. Some 100,000 Americans suffer from this group of inherited retinal diseases.

    In a paper appearing online this week in the early edition of the journal Proceedings of the National Academy of Sciences, University of California, Berkeley, scientists who invented the photoswitch therapy and vision researchers at the School of Veterinary Medicine of the University of Pennsylvania (PennVet) report that blind mice regained the ability to navigate a water maze as well as normal mice.

    The treatment worked equally well to restore light responses to the degenerated retinas of mice and dogs, indicating that it may be feasible to restore some light sensitivity in blind humans.

    “The dog has a retina very similar to ours, much more so than mice, so when you want to bring a visual therapy to the clinic, you want to first show that it works in a large animal model of the disease,” said lead researcher Ehud Isacoff, professor of molecular and cell biology at UC Berkeley. “We’ve now showed that we can deliver the photoswitch and restore light response to the blind retina in the dog as well as in the mouse, and that the treatment has the same sensitivity and speed of response. We can reanimate the dog retina.”

    Advantages over other gene therapies

    The therapy has several advantages over other sight restoration therapies now under investigation, says vision scientist John Flannery, UC Berkeley professor of vision science and of molecular and cell biology. It uses a virus already approved by the Food and Drug Administration for other genetic therapies in the eye; it delivers an ion channel gene similar to one normally found in humans, unlike others that employ genes from other species; and it can easily be reversed or adjusted by supplying new chemical photoswitches. Dogs with the retinal degeneration provide a key test of the new therapy.

    “Our ability to test vision is very, very limited in mice because, even in the healthy state, they are not very visual animals, their behaviors are largely driven by their other senses,” he says. “Dogs have a very sophisticated visual system, and are being used already for testing ophthalmic gene therapy.”

    Benjamin Gaub and John Flannery observing a mouse in a water maze, in which the mouse swims to a platform designated by bright flashing lights. Mervi Kuronen image.

    The dogs were chosen because they have inherited a genetic disease caused by the same gene defect as some people with retinitis pigmentosa. Several of them at PennVet were treated and are currently undergoing tests to determine what degree of light sensitivity they now have.

    “Seeing that some of the UC Berkeley results with this pharmaco-optogenetic strategy that worked so nicely in mice could be reproduced by our group at PennVet in dogs with late-stage retinal degeneration was really exciting,” said William Beltran, an associate professor of ophthalmology at the UPenn School of Veterinary Medicine. “Use of such a clinically relevant large animal model allows us to begin tackling the next challenges on the road to translating this novel therapeutic strategy to human patients.”

    Hybrid chemical-genetic therapy

    Genetic diseases like retinitis pigmentosa destroy the photosensitive cells of the eye, the photoreceptors, but often leave intact the other cells in the retina: the bipolar cells that the photoreceptors normally talk to, and the ganglion cells that are the retina’s output to the brain. Isacoff, Flannery and UC Berkeley colleagues have developed several optogenetic techniques for restoring light-sensitivity to surviving retinal cells other than the photoreceptors. These involve using the adeno-associated virus – a common and harmless vector or carrier for gene therapy – to successfully carry a modified gene into these cells. The virus inserts the therapeutic gene into the cell’s DNA and uses its instructions to produce a receptor protein – a modified version of a common glutamate receptor ion channel – that they display on their surface.

    The researchers then inject a chemical photoswitch into the eye, “basically, a glutamate dangling on a light-sensitive string,” said Isacoff, “which anchors to the modified receptor and stuffs the glutamate into its docking site on the receptor when activated by light.” The newest version of the photoswitch is fast enough to turn the activity of retinal neurons on and off at a rate that approaches video rate of 30 frames per second.

    In mice, they can successfully insert the gene into almost every one of the million or so retinal ganglion cells. This, the researchers say, should restore useful vision.

    “So we have reasonable speed and a lot of pixels, now the question is: What can the treated animals see? So far we can say that the treated mice can distinguish between steady light and flashing light. Our next step is to figure out how good they are at telling images apart,” said Isacoff, who holds the Class of 1933 chair.

    Which cells get gift of sight?

    One key question the researchers wanted to answer is whether it is best to insert photoswitches into ganglion cells or bipolar cells. Viruses can be made to target one or the other. Because activity flowing from upstream bipolar cells to the retina’s output ganglion cells undergoes a lot of processing in the retinal circuit, the researchers were hoping that this same processing would occur when bipolar cells were given a new function they never had before, light-sensitivity.


    NIH funding keeps giving
    The work was funded in part by a nine-year NIH grant for the Nanomedicine Development Center for the Optical Control of Biological Function.
    “The NIH funding got us all the way from designing the chemical photoswitch to an experimental therapy in the dog,” Flannery said, noting the essential role played by a UC Berkeley interdisciplinary team of chemists, molecular biologists and vision scientists.
    “And along the way, we developed tools that could be applied to the basic science of how synapses work and how neural circuits work,” Isacoff added. “These are spinoffs that themselves could have implications for the clinic.”
    These tools are now the basis of new UC Berkeley projects recently funded by NIH and NSF through President Obama’s BRAIN Initiative.


    “When we put the photoswitched channels into bipolar cells and record the output of the ganglion cells, we see complicated patterns that look a lot like the activity you get in a normal retina, compared to the on-off activity you get when you put the same photoswitch into a ganglion cell,” Isacoff said.

    “The dogs’ behavior should show us if there is a functional difference between driving the system from the bipolar cells versus the ganglion cells,” Flannery said.

    He notes that the therapy works only for about a week after a single “charging” with the photoswitch, because the protein and attached chemical get recycled by the cell. While the modified receptors are replaced continually, since the new gene remains forever in the DNA, the chemical photoswitch – maleimide-azobenzene-glutamate, or MAG – must be resupplied by injection into the eyeball. Right now this means injection every week or so, with the future development of a slow release formulation less often.

    “This is not necessarily a disadvantage,” Isacoff said, “because the therapy can be stopped, and new photo-sensitive chemicals can be tried as they are improved.”

    The researchers continue to study the effects of treatment in both mice and dogs, improve the photoswitch, and develop ways of attaching the photoswitch to other receptors, including some that could amplify the signal and allow perception of fainter light, as occurs normally in rods and cones.

    The experiments, analysis and much of the design of the study were performed by first co-authors Benjamin Gaub, a graduate student, and Michael Berry, a technician, along with postdoctoral fellows Michael Keinzler and Andreas Reiner and technician Amy Holt, all from UC Berkeley, and Natalia Dolgova and Sergei Nikonov in the labs of Gustavo Aguirre and William Beltran of UPenn.

    The work was funded by a nine-year grant from the National Institutes of Health for the Nanomedicine Development Center for the Optical Control of Biological Function and by a grant from the Foundation Fighting Blindness, USA.

    See the full article here.

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  • richardmitnick 9:37 am on December 7, 2014 Permalink | Reply
    Tags: , , Genetics,   

    From Nautilus: “In Search of Life’s Smoking Gun” 



    September 18, 2014
    By Jennifer Barone

    It was nearly midnight aboard the research vessel Atlantis. The ship was about a thousand miles west of Costa Rica, where she’d sailed from, hovering over a hydrothermal vent field in the eastern Pacific. Rutgers microbiologist Costantino Vetriani, seated a few feet away from me in the dark control room, radiated energy despite the hour. He peered intently through his glasses at dozens of monitors, occasionally running a hand over his shaved head. On the live video feed from the remotely operated submersible on the bottom, we watched thick black smoke with a scorching temperature of over 350 degrees Celsius billow from a rocky tower a mile beneath us. It was a stunning sight, an underwater pillar releasing a storm of pent-up energy from the dark bowels of the Earth. Vetriani, a trim Italian clad in a T-shirt reading RNA: The Other Nucleic Acid, observed the raw power, his dark eyes shining. “A black smoker is a window into hell,” he said with a grin.

    In fact, the black smoker may be a window into the eruption of life on Earth. Vetriani is part of a team of scientists who have come to the vents to study the microbes that carpet every surface in and around them. Earlier, in the ship’s library, chief scientist Stefan Sievert, a microbial ecologist at Woods Hole Oceanographic Institution, had outlined the goals of the month-long expedition. He explained that understanding how the microbes survive in the hellish vents—what nutrients they use and at what rates; how quickly they turn vent fluids into living biomass—could give insight into how biological life evolved. I was tagging along and assisting with record-keeping during the work on the bottom, which ran 24 hours a day, save the occasional interruption when the seas were too rough to deploy the ROV safely.

    After midnight, as Vetriani and I took in the black smoker, he explained that the hydrothermal vents were “a relic environment, one we believe resembles what the early conditions on Earth might have been. What we’re doing ultimately is trying to understand how life evolved on the planet.” Being aboard the Atlantis allowed me to learn not only about the primeval microbes that live at vents today, but about how organic life may have first arisen in the ocean’s depths. As we watched the thick, hot fluid venting from the mineral chimney, at the timeless place where rock and water meet at the bottom of the sea, it was as if were looking directly into life’s birthplace.

    Engineers deploy the remotely operated vehicle Jason from the fantail of the research vessel Atlantis at a hydrothermal vent site in the eastern Pacific.Jennifer Barone

    Ever since hydrothermal vents were first spotted by geologists diving in the submersible Alvin in 1977, many scientists have believed these deep-sea crucibles could represent the cradle of life. The matter is still far from settled. But vent fluids and the surrounding water bring together essential elements needed for life, such as carbon, hydrogen, oxygen, nitrogen, and sulfur. This combustible mix, scientists believe, may have spawned the precursors of complex molecules, such as RNA, that stirred to life in the first cells.

    Hints of deep-sea vents’ existence came from a 1976 expedition near the Galapagos Islands. An instrument towed near the ocean floor detected a plume of fluid slightly warmer than the cold background seawater. Geologists returned with the submersible the following year and found the smoking seafloor hot springs they’d predicted—along with an utterly unexpected assemblage of living things: clams, giant worms, pink fish, and scuttling white crabs.

    The deep sea at the time was thought to be a biological desert, so no one had expected to need any biologists on the vent expedition. But Jack Corliss, a geologist crouched in Alvin during that first dive to the vents, immediately saw them as a possible site for life’s origins. And hydrothermal systems were probably abundant on the early Earth, which was hotter in its youth. Teaming up with John Baross, a microbiologist who studied some of the earliest microbial samples from vents, and graduate student Sarah Hoffmann, Corliss published the hypothesis in 1980. They proposed that simple organic molecules such as amino acids could form in the hot vent fluids, and eventually such molecules could have been enclosed in a membrane to form a living cell. Baross described vents as “the only contemporary geological environment which may be called truly primeval.”

    As we watched the thick, hot fluid venting from the mineral chimney, it was as if we were looking directly into
    life’s birthplace.

    For all of their extremes of temperature, pressure, and other properties, deep-sea vents may have offered a relatively cozy refuge on the violent world of the early Earth. Our young planet was bathed in much stronger ultraviolet radiation from the sun because it hadn’t yet developed a protective ozone layer. That didn’t come along until after the evolutionary invention of photosynthesis pumped a steady supply of oxygen into our atmosphere.

    And sunburn wasn’t the only challenge at the surface. Geoscientists think that right around the time that life may have been getting started, a little less than 4 billion years ago, our planet endured a heavy bombardment by space rocks. “That would have made the surface and near-surface lethal,” says Robert Hazen, an astrobiologist at the Carnegie Institution for Science and author of The Story of Earth, which describes the planet’s formation and early life. “But down where these hydrothermal systems occur, it was insulated from that kind of trouble.”

    Most important, though, is that vents are bursting with energy. The fluid emanating from them starts out as cold seawater that sinks into cracks and fissures in the seafloor. In the crust, magma heats the water, which picks up dissolved minerals and gases—such as hydrogen and hydrogen sulfide—from the molten rock before shooting back into the ocean. Microbes at vents today use the chemical energy in those fluids to make sugars and other energy-rich molecules that form the base of the food chain.

    “Life needs energy,” Sievert said one bright, breezy afternoon on the ship’s bow, in between our morning and evening shifts in the dark control room. “And there’s plenty of it available at hydrothermal systems. So that’s a good place to start. It’s easy to imagine early organisms thriving with that energy source.”

    CHIP OFF THE OLD VENT: Jason’s manipulator arm breaks off the chimney of a black smoker so researchers can culture and analyze the microbes living in and on it.http://www.whoi.edu

    The hypothesis that biological life began in vents got a boost from the discovery of a new kind of hydrothermal vent. In 1991, geochemist Michael Russell, now at NASA’s Jet Propulsion Laboratory, described magnesium rich mineral deposits in Yugoslavia that he suggested had formed at a vent where the fluids were alkaline, in contrast to the acidic stuff typically found at black smokers and other volcanic vents.

    No one had ever seen alkaline vents like the ones Russell proposed at the time. Then in 2000, marine geologist Deborah Kelley of the University of Washington and colleagues visited the ridge that runs along the floor of the Atlantic Ocean. They were diving in Alvin every day and towing a camera each night. One night someone noticed a strange white tower on the camera feed. Kelley dove on the site two days later and got the first close look at what she named the Lost City.

    Lost City vents form through a chemical reaction between seawater and minerals in iron- and magnesium-rich rocks in the crust. That reaction produces heat energy. As Russell had predicted, it also yields alkaline vent fluids that rise from the seafloor. When those fluids drift up into the ocean, they turn dissolved carbon dioxide into limestone structures that may have housed the beginnings of life.

    Origin-of-life scientists perked up as they learned more about the properties of the warm springs of the Lost City. One big attraction is the presence of an ion gradient—a key ingredient in just about every known form of life—between the vent fluids and the seawater. The alkaline fluids are basic, with a pH (a measurement of acidity and alkalinity levels) of around 10 or 11, meaning they have a low concentration of protons. Seawater, with a pH of around 8, is less alkaline—that is, slightly more acidic—so it has more protons than the vent fluids.

    That geochemistry caught scientists’ attention because an ion gradient—a difference in the concentration of ions from one place to another—is one of the universal properties of living things and a fundamental part of how cells get their energy. It provides conditions that could be a brewery for early life.

    “What just about all of life is doing is producing a proton gradient and then using the flow of those protons across a membrane to generate chemical energy,” says Nick Lane, a biochemist at University College London and author of Life Ascending, about the origin and evolution of life. The general pattern holds true for mitochondria, which are the intracellular generators that power our own cells, as well as for most free-living microbes.

    This combustible mix may have spawned the precursors of complex molecules, such as RNA, that stirred to life in the first cells.

    The system operates a bit like a hydroelectric dam, Lane explains. A biological pump, in the form of a protein, moves an abundance of protons to one side of a membrane. Then the protons are allowed to flow back across the membrane through another protein that acts as a turbine. The turbine produces ATP, or adenosine triphosphate, the molecule that carries the biochemical energy that powers a cell’s activities.

    The specific proteins and membranes vary widely across different forms of life. But the proton gradient is present in just about every life form ever studied. Some researchers see that universality as circumstantial evidence that such a gradient must have been present in the environment where life was born. “It’s very difficult to explain why all of these organisms share this trait unless you can point to some geochemical source of these gradients in the environment where life got started,” says evolutionary biologist Bill Martin of the University of Dusseldorf. “And then, boy do those alkaline hydrothermal vents start to look really good.”

    So how might life have bootstrapped its way into existence at a hydrothermal vent like those at the Lost City—or those dotting the Pacific directly beneath the Atlantis? One possible scenario is that reactions between some of the simple chemical compounds at a vent—like carbon dioxide and hydrogen—generated organic molecules, which became increasingly complex.

    Essentially, the vent would have acted as a natural hydrothermal reactor. For example, reactions between carbon dioxide and hydrogen, catalyzed by minerals found in the vents, can form a molecule known as pyruvate. Pyruvate is a precursor of many amino acids, which in turn can link together to create proteins. Carbon dioxide and hydrogen can also form formaldehyde, which can react with itself to form ribose, a sugar that’s a component of RNA. Hydrogen cyanide, which has been found at vents, can react with itself to form ringed structures known as bases, another RNA ingredient. Ribose, a base, and a phosphate group (also available at vents) join together to form a molecule called a nucleotide. String several nucleotides together, and you have a strand of RNA. Pores within the vent structures might have played the role of membranes, concentrating the organic molecules such as RNA and amino acids in a small space.

    Eventually RNA would begin to self-replicate, a process governed by natural selection. Somewhere along the line, perhaps around 4 billion years ago, the young proto-life inhabiting the vent pores would have acquired DNA, perhaps by making a few chemical tweaks to RNA. (Removing an oxygen atom transforms ribose to deoxyribose, and the addition of a methyl group toggles the single base that differs between DNA and RNA). From there, would-be life would need to assemble a membrane for itself and generate its own ion gradient that could be used to produce energy in the form of ATP. At that point, it could be considered the first cell.

    PRIMEVAL PROBE: A sensor analyzes fluid chemistry at a vent colonized by giant tube worms (red plumes) and mussels (yellow).http://www.whoi.edu

    Aboard the Atlantis, a batch of samples from the vents broke the surface, and Vetriani joined the swarm of scientists that descended on it after a crane deposited the haul on deck. He reached into a seawater-filled box and pulled out a black smoker chimney, glittering with pyrite, collected from the bottom, along with a bacterial sampling cylinder made of PVC and mesh. Then he hurried into the ship’s lab, where he and his collaborators began processing the samples.

    Many of the microbes that Vetriani and Sievert recovered turned out to be Epsilonproteobacteria, a group of organisms that tend to dominate at vents but not at any other environment on the planet. The pair found that some of these bugs don’t tolerate oxygen and use a metabolic pathway that allows them to “breathe” using sulfur, which is present in abundance at vents. “This sulfur metabolic pathway might have been a core ancestral pathway,” Vetriani said, because it relies exclusively on raw materials thought to have been present on the early Earth and eschews those not thought to have been available.

    What concrete evidence did the analysis of these primeval microorganisms provide about life’s origins? Vetriani said he was not comfortable giving an answer. Research into the cradle of life is essentially in its own infancy. “A few decades ago, we didn’t even know life could survive at some of these high temperatures,” Vetriani said. “The origin of life means going back to abiotic processes that might have occurred before the first cell assembled. We’re getting as close as we can by studying these vent organisms to understand what might be those early metabolic pathways. They may be the closest we have to the organisms that might have been living on Earth billions of years ago. The bottom line is the vents are an environment dominated by volcanic activity, which might resemble that of Earth before photosynthesis evolved. We believe that without oxygen, maybe in a volcanic environment, early organisms might have arisen.”

    On the ship, as I spent morning after night after morning in the cold, monitor-filled control room, logging what kinds of samples were collected and where, I waited for the sight of the giant smokestacks on the seafloor to grow old, but even after a month, it never did. I’m grimly aware that no matter what happens aboard the Atlantis or in the labs on shore, certainty about the origin of life may always be just out of reach. But now I understand the pull that draws explorers back to this place again and again, hoping each time to get a little closer to our own beginnings.

    See the full article here.

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  • richardmitnick 9:16 am on December 7, 2014 Permalink | Reply
    Tags: , , Genetics,   

    From Nautilus: “If the World Began Again, Would Life as We Know It Exist?” 



    June 19, 2014
    By Zach Zorich
    Illustration by Daniel Zender

    Experiments in evolution are exploring what would happen if we rewound the tape of life.

    In less than five milliseconds, a Hydromantes salamander can launch its tongue—including the muscles, cartilage, and part of its skeleton—out of its mouth to snag a hapless insect mid-flight. Among amphibians, it is the quick draw champ. Frogs and chameleons are comparative slowpokes when it comes to their ballistic anatomies. “I’ve spent maybe 50 years studying the evolution of tongues in salamanders,” says David Wake, an evolutionary biologist at the University of California, Berkeley, “this is a particularly interesting case because salamanders, who don’t do anything fast, have the fastest vertebrate movement I’m aware of.” Within their lineage, evolution found a better way to accomplish tongue-hunting. Their seemingly unique adaptation appears to have evolved independently in three other unrelated salamander species. It is a case of convergent evolution—where different species separately developed similar biological adaptations when faced with the same environmental pressures. Salamanders are Wake’s go-to example when asked a decades-old question in evolutionary biology: If you could replay the “tape of life” would evolution repeat itself? In the salamanders, it appears it has: In other organisms, it may not have.

    This question was famously posed by the late evolutionary biologist Stephen Jay Gould in his 1989 book, Wonderful Life: The Burgess Shale and the Nature of History, which was published at a time when people still listened to music recorded on cassette tapes.1 The book discussed fossils left behind by myriad strange animals that inhabited the Earth’s oceans about 520 million years ago during the Cambrian period, and were preserved in the Burgess Shale. Nearly all animals alive today can trace their lineages back to the creatures that lived in the Cambrian, but not every animal that lived in the Cambrian period has descendants that live today. Many Cambrian species have since died out because they weren’t fit enough to compete, or because they were in the wrong place at the wrong time during volcanic eruptions, asteroid impacts, or other extinction events.

    Gould saw the incredible diversity of the Burgess animals and theorized that life today would have been different had history unfurled in another way. Random mutations and chance extinctions—events Gould called “historical contingencies”—would build on each other, he suggested, driving the evolution of life down one path or another. In Gould’s view, the existence of every animal, including humans, was a rare event that would have been unlikely to re-occur if the tape of life were rewound to the Cambrian period and played again. One of the paleontologists—Simon Conway Morris of Cambridge University—whose work on the Burgess fossils was heavily cited by Gould in his book, strongly disagrees with this viewpoint.

    In Gould’s view, the existence of every animal, including humans, was a rare event that would have been unlikely to re-occur if the tape of life were rewound to the Cambrian period and played again.

    Conway Morris believes that, over time, natural selection leads organisms to evolve a limited number of adaptations to the finite number of ecological niches on Earth. This causes unrelated organisms to gradually converge on similar body designs. “Organisms have to configure themselves to the realities of the physical, chemical, and also biological world,” he says. In Conway Morris’s view, these constraints make it all but inevitable that if the tape of life were replayed, evolution would eventually reproduce organisms similar to what we have today. If humans’ ape ancestors had not evolved big brains and the intelligence that goes with them, he believes that another branch of animals, such as dolphins or crows, might have, and filled the niche that we now occupy. Gould disagreed.

    Both scholars recognized that convergence and contingency exist in evolution. Their debate instead revolved around how repeatable or unique key adaptations, like human intelligence, are. Meanwhile, other biologists have taken up the puzzle, and shown how convergence and contingency interact. Understanding the interplay of these two forces could reveal whether every living thing is the result of a several-billion-year-long chain of lucky chances, or whether we all—salamanders and humans alike—are as inevitable as death and taxes.

    Creatures of the deep: An artist’s rendering of Opabinia. Similar to an elephant’s trunk, its long proboscis was likely used to scavenge the seafloor for food and pass it back to the creature’s bizarre, backwards-facing mouth. Nobu Tamura

    Rather than attempt to reconstruct history with fossils, Richard Lenski, an evolutionary biologist at Michigan State University, decided to watch convergence and contingency unfold in real time, in the controlled environment of his laboratory. In 1988, he separated a single population of Escherichia coli bacteria into 12 separate flasks containing liquid nutrients, and let them each evolve separately. Every few months for the past 26 years, he or one of his students has frozen a sample of the bacteria. This archive of frozen microbes gives Lenski the ability to replay E. coli’s tape of life from any point he wishes, simply by thawing out the samples. Along the way, he can examine how the bacteria change both genetically and in ways that are visible under a microscope. Lenski says, “The whole experiment was set up to test how reproducible evolution was.”

    In 11 of Lenski’s flasks, the E. coli cells grew physically larger, but bacteria in one flask divided itself into separate lineages—one with large cells and the other with small cells. “We call them the smalls and the larges,” says Lenski. “They have coexisted now for 50,000 generations.” No other population in the experiment did the same; a historically contingent event seemed to have taken place. Even 26 years later, none of the other E. coli lineages evolved it. In this case, contingency seems to have won out over convergence.

    In 2003, another contingent event took place. The number of E. coli in one of the flasks increased to the point where the normally translucent nutrient solution turned cloudy. At first Lenski thought that the flask had been contaminated, but it turned out that the E. coli, which normally just feed on glucose in the solution, had developed a way to consume a different chemical in the flasks, called citrate. After 15 years, or 31,500 generations, just one of the populations was able to consume the substance.2 Its population size quickly expanded by a factor of five.

    This “historical contingency” gave Lenski and his graduate student Zachary Blount a chance to examine the likelihood that it would happen again if they rewound the tape. Blount went to the archive of frozen E. coli, and selected 72 samples collected at different periods in the experiment from the population that later evolved citrate metabolism. He thawed them out, and let them grow. Eventually, four out of the 72 samples acquired the ability. What’s more, the mutations only occurred in populations that had been frozen after 30,500 generations. Genetic analysis showed that several genes had undergone mutations that “potentiated” the evolution of citrate metabolism before that point. In other words, the ability to consume citrate was contingent upon other mutations that had come before it. Those formed a fork in the road, altering the path that generations after would be able to travel.

    The early, bad mutations were essential to the fitness of later generations, perhaps because they added to the genetic variation that later random mutations could act upon.

    The Long-Term Evolution Experiment, as the E. coli project is known, has surpassed 60,000 generations now, giving Lenski a deep data set from which to draw inferences about the interplay of contingency and convergence in evolution. Subtle changes in the bacteria’s DNA that make them larger and better able to proliferate in the flask have been relatively common across the groups. At the same time, Lenski has witnessed “striking” cases of contingency, in which one population did something completely different than the others. But as in convergence, he adds, these transformations weren’t entirely random.

    “Not everything is possible,” no matter the process, Wake explains. “Organisms evolve within the framework of their inherited traits.” Organisms can’t pass on mutations that kill them or prevent them from reproducing. In the case of Hydromantes salamanders, their ancestors had to overcome a serious limitation: To acquire their ballistic tongues they had to lose their lungs. That’s because their tongue partly derives from muscles that their predecessors instead used to pump air into the lungs. Now, that formerly small and weak muscle is much larger and stronger. It wraps like a spring around a tapered bone at the back of the mouth, and when the muscle squeezes, the bone generates the force that fires the tongue along with its bones out of the mouth. So, Hydromantes’ ancestor did not simply acquire a mutation and evolve a fast ballistic tongue. Instead, the adaptation followed a series of mutations that first enabled the creature to overcome its reliance on lungs for oxygen and buoyancy control. Each change was contingent on the one before it.

    Chameleons, on the other hand, retain their lungs. Instead of re-tooling their lung anatomy, they have evolved a piece of collagen that allows them to catapult their tongues at prey. On the surface, salamander and chameleon tongues converge, but not upon closer inspection. It takes a chameleon 20 milliseconds to shoot its tongue at its prey, a positively glacial pace when compared to the Hydromantes’ five-millisecond firing time. Why are chameleons stuck hunting with such slow tongues? The answer is that they have encountered a kind of obstacle to convergent evolution. The chameleon’s tongue is fast enough to ensure their survival, but they lack the “framework of inherited traits” to evolve the salamanders’ deadlier ballistic anatomy. The chameleons have reached what biologists call an “adaptive peak.”

    In experiments with viruses that infect bacteria, called bacteriophages, Harvard biologist David Liu discovered adaptive peaks as well. These peaks limit the ability of organisms to converge on a single, optimal design. They help explain why contingencies aren’t often repeated.

    Liu wanted to know whether identical groups of bacteriophages could separately evolve a particular enzyme if he put the same pressures on them. He quickened the rate of protein evolution within the viruses, using a system he calls PACE.

    During the course of the experiment, the viruses that could not make the enzyme Liu was looking for were removed from the study: Those that achieved the goal, remained. Of those, some had “better” enzymes than others.3 Specifically, the enzyme they made, a polymerase, recognizes a certain DNA sequence and helps turn it into RNA—some polymerases recognized that sequence very precisely and others less so. Like the chameleons’ relatively slow ballistic tongue, these viruses evolved an adaptation that allowed them to survive, but it also prevented them from gaining an even better polymerase. Some viruses were stuck on a lower peak, while a few had climbed to higher ones.

    To understand what biologists mean by adaptive peaks, imagine a landscape in which the topography represents the highs and lows of reproductive potential. In the case of Liu’s bacteriophages, different populations searched this landscape through the acquisition of various mutations. Some landed beside small mountains and a few beside Mt. Everest-like peaks. The higher they climbed up their respective mountains, the easier it was to survive. So, they ascended the slope before them. Once at the top of a small peak, viruses could not then move to a taller, more optimal, one. In order to get there, they would need to climb back down, reducing their ability to survive every step of the way. That is a serious challenge because survival of the fittest is a present concern. Which mutation occurs first—which adaptive peak an organism begins to climb—is an historical contingency that convergent evolution can have a very difficult, if not impossible, time overcoming.

    What’s true for E. coli is also true for some microbe anywhere in the universe.

    The timing of mutations mattered. “Early random events that create differences in the gene pool can have profound effects in determining whether an ultimately beneficial mutation is allowed to effect the survival of an organism,” Liu says. “That randomness erodes the reproducibility of evolution.” In this experiment, contingency had won out over convergence. Past events prevented repeatability.

    One way that life may overcome the limitations of adaptive peaks was revealed in studies of digital organisms conducted by Michigan State University computational biologists Chris Adami and Charles Ofria. The duo created a computer program called Avida in which digital organisms evolve under environmental conditions set by the experimenter. Avidians mutate by randomly gaining and losing pieces of code that may allow them to solve math problems, which increases their ability to reproduce.

    In one experiment, the Avidians were set to the task of evolving the ability to solve a complex logic problem called “bitwise equals.” Only four out of the 50 digital populations evolved the code necessary to complete the operation.4 All of the successful populations were ones that initially carried a lot of mutations (random pieces of computer code) that made it harder for them to solve math problems and therefore reproduce. It seems counterintuitive, but Ofria found that the early, bad mutations were essential to improving the fitness of later generations, perhaps because they added to the genetic variation that later random mutations could act upon.

    Ancient grazers: A recreation of Aysheaia pedunculata made from a fossil. These caterpillar-sized creatures are thought to have grazed on ancient sea sponges.Citron / CC-BY-SA-3.0 – Eigenes Werk

    Does the rarity of any particular sequence of events imply that major shifts in evolution are unlikely to be repeated? The experiments suggest that’s true, but Conway Morris firmly answers, no. “You’d be daft to say that there aren’t accidents of one sort or another. The question is one of time scales,” he says. Given enough years and enough mutating genomes, he believes that natural selection will drive life toward the inevitable adaptations that best fit the organisms’ ecological niche, no matter the contingencies that occur along the way. He believes that one day, all of the E. coli in Lenski’s experiment would evolve to consume citrate, and that all of Liu’s viruses would eventually scale their adaptive Mount Everests. Further, those experiments were conducted in very simple and controlled environments that don’t come close to matching the complex ecosystems that life must adapt to outside the lab. It’s hard to say how real-world environmental pressures might have altered the results.

    So far, the biggest shortcoming in all of the attempts to answer the “tape of life” question is that biologists can only draw conclusions based on just one biosphere—the Earth’s. An encounter with extra-terrestrial life would undoubtedly tell us more. Even though alien organisms may not have DNA, they’d likely show similar patterns of evolution. They would need some material that would be passed down to their descendants, which would guide the development of organisms and change over time. As Lenski says, “What’s true for E. coli is also true for some microbe anywhere in the universe.”

    Therefore, the same interactions between convergence and contingency might play out on other planets. And if extraterrestrial life faces similar evolutionary pressures to life on Earth, future humans may discover aliens that have convergently evolved an intelligence like ours.5 On the other hand, if contingent events build on one another, driving the development of life down unique paths as Gould suggested, extra-terrestrial life may be extraordinarily strange.

    Gould believed that humans represented a “wildly improbable evolutionary event,” As evidence, he pointed to the fact that human-like intelligence has only evolved once in 2.5-billion years of life on Earth. He saw the likelihood of another species evolving intelligence similar to our own as vanishingly rare. The idea that we may be the sole sentient species in the universe carries with it some important implications that go beyond biology. “Some find the prospect depressing;” he wrote in Wonderful Life, “I have always regarded it as exhilarating, and a source of both freedom and consequent moral responsibility.”

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Welcome to Nautilus. We are delighted you joined us. We are here to tell you about science and its endless connections to our lives. Each month we choose a single topic. And each Thursday we publish a new chapter on that topic online. Each issue combines the sciences, culture and philosophy into a single story told by the world’s leading thinkers and writers. We follow the story wherever it leads us. Read our essays, investigative reports, and blogs. Fiction, too. Take in our games, videos, and graphic stories. Stop in for a minute, or an hour. Nautilus lets science spill over its usual borders. We are science, connected.

  • richardmitnick 8:51 am on December 7, 2014 Permalink | Reply
    Tags: , Genetics,   

    From Nautilus: “Creating Life As We Don’t Know It” 



    October 24, 2013
    By Carl Zimmer
    Illustration by Emiliano Ponzi

    Back in the 1970s, you might open up a box of cereal one morning and out would fall a cardboard disk. It was a code wheel, which allowed preteen cryptographers to ply their trade. The wheel had two disks of unequal size, joined at the center, so that you could turn each of them on the common axis. Letters ringed the outer wheel, and the inner wheel was marked with an arrow. If you lined the arrow up with a letter, a window in the inner wheel revealed a different letter. You could write out a message in those coded letters that would look like gibberish to outsiders (most importantly, to your parents). The only way to understand the message was to decipher it with the help of another code wheel from another box of cereal—provided, of course, it was the same brand.

    The image of that code wheel always comes back to mind whenever I page through a biology textbook and see this:


    It is a code wheel of sorts. But it’s not for encrypting messages like, Meet me in the backyard with the Micronauts. It’s a code wheel that exists in our own bodies, in every one of our 30 trillion cells1, enabling them to translate the recipes stored in our DNA into the stuff we are made of. You can find the same code wheel in pretty much identical form in every species on Earth. It is, when you get down to it, the code of life.

    This genetic code is different from an organism’s specific genetic sequence—a much more familiar concept. Take the genome of the gorilla. It is stored in the ape’s DNA, consisting of a series of chemical units called bases, each one like a letter in a book. In the case of the gorilla, that book is 3.04 billion letters long, comprising 21,000 genes.

    To translate the gorilla’s genes into the corresponding proteins2 that build and do almost everything in the gorilla’s body, its cells use a set of rules: the genetic code. A genetic sequence is a book, but without the code, it’s meaningless—like hieroglyphics without the Rosetta stone.

    Scientists cracked the genetic code in the 1960s. It was one of modern biology’s great triumphs, on par with the discovery of DNA’s double-helix structure. It enabled scientists to engineer organisms with new genes, opening the way for our age of biotechnology.

    Five decades later, the genetic code still enchants scientists. They continue to debate how it evolved, and why there aren’t lots of different codes. And as they come to better understand the history of the genetic code, scientists are creating a future for it. They are re-coding cells to build new kinds of proteins never seen in nature, which could be the basis for new kinds of medicine.

    This research goes beyond the advances in biotechnology we see routinely in the news—reading genes, for example, or fine-tuning the proteins they encode. It changes the biological meaning of DNA. By re-coding life, scientists may eventually engineer new kinds of organisms fundamentally different from anything that’s existed on Earth over the past 4 billion years—a kind of alien life created in the lab.

    A Mysterious Mess

    When Francis Crick and James Watson published the structure of DNA in 1953, they solved many mysteries about life in one fell swoop. Earlier generations of scientists had puzzled over the chemistry that could make heredity possible. DNA provided an elegantly simple answer. It was made of two backbones, along which were arrayed a series of bases. DNA needed only four bases—abbreviated as A, C, G, and T—to produce all of life’s diversity. One combination of bases gives you a gorilla. Another, a sunflower.

    But despite this triumph, Crick and Watson had no idea how a cell could use its DNA to build proteins. What made this mystery particularly baffling was that proteins are based on a different kind of chemistry from genes. While DNA is composed of bases, proteins are made from 20 different Lego-like compounds called amino acids that snap together to form long, flexible chains.

    When the Russian-born scientist George Gamow read Watson and Crick’s paper, he immediately recognized that this puzzle was a matter of cryptography.. DNA contained messages composed from a four-letter alphabet. Proteins were sequences, too, but they were composed from a different alphabet with 20 letters. Somehow, that four-digit system could store information for making all the proteins in our bodies—from our muscles to our neurotransmitters to our digestive enzymes. “Thus the question arises about the way in which four-digital numbers can be translated into such ‘words,’ ” Gamow later wrote.

    To answer that question, Gamow approached it much as British cryptographers had when they cracked Nazi Germany’s Enigma machine a decade earlier. Rather than running a biology experiment, Gamow relied on logic. He proposed—with no hard evidence—that proteins formed when amino acids dropped into holes in DNA molecules. Here’s how Gamow pictured this (the bases, wrapping around the double helix of DNA, are shown as circles. The diamonds are the holes for amino acids):


    Gamow proposed that only one type of amino acid could fit between a given assemblage of bases. He calculated that there were 20 different diamonds, which would perfectly fit the 20 different amino acids.

    Surely that couldn’t be a coincidence, Gamow suggested.

    While Gamow’s answer was elegantly clean, it was completely wrong. The right answer eventually turned out to be almost clumsily baroque: Cells make proteins by first making a single-stranded copy of a gene, called messenger RNA. A molecular factory called a ribosome grabs the messenger RNA and reads its sequence, plucking amino acids floating around the cell to build the protein specified by the DNA.

    The ribosome reads three bases at a time to pick out each new amino acid, and each of these triplets is called a codon.

    Here again is the wheel that illustrates the genetic code. It represents all the codons in the genetic code, starting from the center and moving outward. GUA, for example, encodes valine.

    The biggest surprise about the genetic code is that more than one codon can encode the same amino acid. Not only does GUA encode valine; so do GUC, GUG, and GUU3. Other amino acids are encoded by three codons, others by two. Only a few amino acids are encoded by a single codon. It’s a far cry from the sleek, one-to-one code Gamow dreamed of. The real genetic code seems like a spectacular mess.

    If I had gotten a cereal-box code wheel that worked this way, I’d have written to General Foods for a refund.

    One Code to Rule Them All

    To crack the genetic code, scientists started out studying the gut bacteria E. coli. They chose that particular microbe because generations of scientists before them had studied it, assembling a massive kit of tools for dissecting its biochemistry. Once they finished working out E. coli’s genetic code, they began examining other species. In case after case, the scientists found the exact same quirky system.

    Ever since the discovery of the genetic code, scientists have wondered how we ended up with this universal, sloppy arrangement. Some researchers have argued what seems like sloppiness is actually ruggedness—that natural selection favored the genetic code because it was more resilient than earlier versions. By using more than one codon for an amino acid, an organism can defend itself against harmful mutations.

    When the Russian-born scientist George Gamow read Watson and Crick’s paper, he immediately recognized that this puzzle was a matter of cryptography.

    If GUC mutates to GUU, for example, our cells don’t switch to a different amino acid and thus create a defective protein. It picks valine in either case. In one study, researchers created a vast number of random genetic codes and measured how well they withstood mutations. The real genetic code ranked in the top 0.000001 percent of all possible codes.

    Other scientists disagree with this literal one-in-a-million view of the genetic code, saying there may be nothing special at all about it. In 1968, Crick proposed that the genetic code arose through a process he lyrically dubbed a “frozen accident.”

    Crick argued that the earliest forms of life had primitive, sloppy genetic codes. Cells would frequently make mistakes as they deciphered codons, grabbing a different amino acid. Because their proteins were small and simple, these early life-forms could make do with defective ones.

    Over time, microbes emerged with more precise codes. The chances that a cell would misread a particular codon fell. They also started using many more amino acids, allowing them to build more complex and useful proteins.

    Eventually, Crick argued, the cells got so complex that tinkering with their genetic code became very risky: One mutation might make a cell churn out defective versions of hundreds of different proteins, leading to catastrophic failure. The evolution of the genetic code screeched to a halt.

    Other researchers, like Nigel Goldenfeld of the University of Illinois, see the code more like a language that made it possible for different species to use the same genes, a biological lingua franca. Microbes sometimes pick up genes from other species, and sometimes the genes prove to be a huge boon. Inside our bodies, for example, antibiotic-resistant bacteria can donate their genes for fending off drugs to vulnerable species. But the only way that borrowed genes can provide a benefit is if a cell can decode them.

    Over millions of years, Goldenfeld argues, life’s many genetic codes gravitated toward each other, enabling a worldwide commerce in DNA, until a single code was left.

    Code Cat and Mouse

    Decades after the discovery of the universal genetic code, scientists found out that it wasn’t exactly universal. In 1992, researchers discovered an exception to the genetic code’s rules. It was an exception lurking in our own cells.

    The vast majority of human DNA is stored within the cell in a sac called the nucleus, but a few scraps of DNA lurk inside small, fuel-producing structures called mitochondria. Mitochondria are like miniature cells inside our cells, decoding their own genes with their own ribosomes. (They most likely started out as miniature cells of their own, in fact—their ancestors were probably free-living bacteria that invaded our cells more than 2 billion years ago.)

    While studying mitochondria, scientists stumbled across a surprising discovery: Their code did not quite match the code for DNA in the nucleus. Normally, for example, UGA gives a ribosome the order to stop making a protein and release it. In human mitochondria, UGA is no longer a “stop codon”: Here, it encodes the amino acid tryptophan.

    Crick proposed that the genetic code arose through a process he lyrically dubbed a “frozen accident.”

    Since that first discovery, researchers have found 34 cases of alternative genetic codes. Each case was the result of an evolutionary modification of the ancestral code. Ken Miller, a cell biologist at Brown University, likens these variations to dialects. “The differences in spelling and word meanings between the American, Canadian, and British dialects of English reflect a common origin. Exactly the same is true for the universal language of DNA.”

    In almost every known alternate genetic code, one codon has been reassigned from one of the standard 20 amino acids to another. But a few species have expanded the code to include new amino acids not used by other life-forms. Certain microbes have switched one of their codons to an amino acid known as selenocysteine. Others have added pyrrolysine. Some species have added both of them to their repertoire.

    These genetic dialects have created a puzzle for biologists. The species with alternative genetic codes are very distant relatives of one another—they reside on far-flung branches of the tree of life. That means that evolution has, over and over again, changed the genetic code.

    In 2009, Edward Holmes, an evolutionary biologist then at Penn State University, and his colleagues discovered something else that these species had in common—something that might be a force that could drive the evolution of an alternative genetic code. When the researchers looked at all the species known at the time to have an alternative genetic code, there was no evidence that a virus could infect any of them.

    Holmes and his colleagues proposed that escaping viruses is what drives some species to change their genetic code. While viruses can be exquisitely deadly to their hosts, they also depend on their hosts for their survival. Typically made up of nothing more than genes encased in a protein shell, viruses don’t have ribosomes or the other components required to make proteins or genes. To replicate, they invade a cell and trick it into reading out the virus’s genes.

    In order to successfully infect a host, though, viruses have to use the same code as their host. If their code doesn’t match, a host cell will produce defective virus proteins, and the new viruses won’t be able to survive.

    “The differences in spelling and word meanings between the American, Canadian, and British dialects of English reflect a common origin. Exactly the same is true for the universal language of DNA.”

    When a deadly new virus epidemic breaks out, the viruses are likely to eradicate most of the hosts. A mutant host with an alternative genetic code may be more likely to survive, because the viruses can’t exploit them. They survive and rebuild the population. And from then on, the host species is immune to all viruses, thanks to their alternative genetic code.

    Earlier this year, however, scientists at the University of Buffalo discovered the first virus that infects a species with an alternative genetic code. Its host is a species of yeast in which CUG has changed from coding one amino acid (leucine) to another (serine).

    When the researchers looked closely at the virus’s DNA, they saw that the CUG codon is almost entirely missing. Once the yeast altered its code, it seems, the virus changed its own genetic messages so that they wouldn’t get garbled. By getting rid of CUG the virus eliminated the risk of producing faulty viruses. Evolving an alternative genetic code is a good way to evade viruses, but it may not guarantee immunity.

    Some of the viruses may be able to catch up.

    Life’s New Master Code Makers

    The discovery of the genetic code in the 1960s permeates our everyday lives 50 years later. Once scientists realized that humans and E. coli used the same code to decipher their genes, they wondered if the microbe could make proteins from human DNA. Herbert Boyer and his colleagues figured out how to snip out a gene for insulin from human cells and insert it into the bacterium. Just as they’d hoped, the microbes began to churn out insulin. Today millions of people with diabetes inject themselves with insulin that was made by bacteria.

    Scientists are becoming more and more adept at using the genetic code to produce valuable molecules. They can make goats produce spider silk in their milk. They can tweak genes to make new proteins, such as tailor-made antibodies designed to attack certain pathogens. All these feats are possible because of life’s lingua franca.

    Yet the genetic code also puts limits on biotechnology’s creativity. It encodes only 20 amino acids. There are hundreds of other amino acids in nature (even some seen in interstellar space) that were never incorporated into life. What’s more, scientists can synthesize unnatural amino acids of practically infinite variety. If scientists could reprogram the genetic code to include these other amino acids, it would open up a universe of possibilities for how to control life.

    The fact that nature has already tweaked the genetic code gave researchers the confidence to try to alter it some more. They carried out their first attempts in the early 2000s. In one such study in 2002, Peter Schultz, a chemist at the Scripps Research Institute, and his colleagues created proteins that are sensitive to light.

    Scientists are becoming more and more adept at using the genetic code to produce valuable molecules. They can make goats produce spider silk in their milk.

    Schultz and his colleagues managed this feat by joining an ordinary amino acid (phenylalanine) and a photosensitive compound called a benzophenone. A flash of UV light gives benzophenones a jolt of energy that lets them bond to a nearby protein.

    Next they changed the molecules in the cell so that instead of reading UGA as a stop codon, they would instead code for the novel benzophenone-carrying amino acid. Schultz and his colleagues then added the genes to E. coli. They allowed the bacteria to make proteins, which they then harvested. When the researchers flashed UV rays at the proteins, some of them joined together, thanks to the bonds formed by their benzophenones. The bacteria had made molecules no organism had ever made before.

    Schultz went on to help found a company called Ambryx based on such experiments, and in 2012, they inked a $303 million deal with pharmaceutical giant Merck to explore new ways to make drugs by altering the genetic code.

    In one typical project, they’re trying to develop anti-cancer molecules that act like guided missiles against tumors. The researchers hope to improve an existing class of drugs made from proteins known as monoclonal antibodies. These antibodies can be engineered to attack only cells that have turned cancerous. Standard monoclonal antibodies stick to cancer cells and make them more conspicuous to immune cells, which can then kill them.

    Ambryx researchers are investigating how to make these antibodies themselves do the dirty work. They are fashioning unnatural amino acids that carry toxins and engineering microbes that can build these toxin-carrying amino acids into the antibodies. Their hope is that once these unnatural antibodies attach to cancer cells, their toxins will immediately kill the cells.

    For now, expanding the genetic code is only a promising technology, not a salvation. Merck does not have tanks full of E. coli churning out cancer drugs. No one knows how efficiently bacteria can make these unnatural proteins.

    It’s possible that more radical changes to the genetic code could end up being more successful. Farren Isaacs, a biochemist at Yale, and his colleagues are running one such ambitious project. Instead of one new codon, they want to alter dozens. If they succeed, they may create organisms that build profoundly new proteins. Their re-coded microbes would be unlike anything alive today—and perhaps unlike anything that has ever existed on Earth.

    Isaacs wants to take advantage of the tremendous redundancy of the genetic code. Instead of using four different codons for the amino acid arginine, he would like to rewrite an organism’s DNA so that it uses only one. That revision would free up three codons he could engineer to encode unnatural amino acids. With 44 redundant codons in the standard genetic code, this strategy could open up vast new biological possibilities.

    In a study published earlier this month in Science, Isaacs and his colleagues took the first step on this path. They used new gene-editing tools to search for every instance in the E. coli genome of the stop codon comprising the sequence UAG: It turned out there were 314. Isaacs and his colleagues surgically replaced 314 UAGs with the sequence UAA, another stop codon. The bacteria did perfectly well without the redundant version.

    This experiment marks the first time researchers have ever changed a codon across an organism’s entire genome. And it now leaves UAG free to encode a new amino acid, enabling scientists to add TAG codons to many different genes. If this method works, they might be able to do the same with other redundant codons, too.

    Rewriting the genetic code this way might allow scientists to do more than just create new kinds of molecules. Today, biotechnology operations are beset by viruses, which kill the microbes scientists use to produce new molecules. Isaacs’s re-coded microbes might be made immune to viruses, which could no longer hijack their ribosomes.

    A new genetic code might also make it possible to eliminate the risk that engineered microbes could escape from labs to wreak havoc. Scientists might be able to engineer the microbes to depend on unnatural amino acids for their survival. Should they escape the lab, they would find only natural amino acids and die. These altered species would, in other words, become slaves to our code, fundamentally divorced from the natural code used by the rest of the living things on our planet.

    Today’s controversies over genetically modified food are fueled by the notion that we have suddenly started tampering with DNA in a dangerous way. In fact, we have been tinkering with DNA for thousands of years, ever since we started domesticating crops and livestock. The genes of a juicy cob of corn are quite different from those in its hard-seeded teosinte forerunners. Biotechnology has enabled us to move genes from one species to another with greater skill in recent decades, and scientists are even starting to edit individual bases of DNA to fine-tune genes.

    But as weird as a microbe with a human insulin gene may seem, it still uses the ancient code that life has relied on for billions of years. We may now be on the verge of an entirely new era—one where we, not natural evolution, control the code of life.

    See the full article here.

    Please help promote STEM in your local schools.

    STEM Icon

    Stem Education Coalition

    Welcome to Nautilus. We are delighted you joined us. We are here to tell you about science and its endless connections to our lives. Each month we choose a single topic. And each Thursday we publish a new chapter on that topic online. Each issue combines the sciences, culture and philosophy into a single story told by the world’s leading thinkers and writers. We follow the story wherever it leads us. Read our essays, investigative reports, and blogs. Fiction, too. Take in our games, videos, and graphic stories. Stop in for a minute, or an hour. Nautilus lets science spill over its usual borders. We are science, connected.

  • richardmitnick 6:48 pm on November 26, 2014 Permalink | Reply
    Tags: , , , Genetics,   

    From Quanta: “New Twist Found in the Story of Life’s Start” 

    Quanta Magazine
    Quanta Magazine

    November 26, 2014
    Emily Singer

    All life on Earth is made of molecules that twist in the same direction. New research reveals that this may not always have been so.

    The mirror-image asymmetry of life is one of the biggest mysteries in biology.
    Brendan Monroe for Quanta Magazine

    For 30 years, Gerald Joyce has been trying to create life. As a graduate student in the 1980s, he studied how the first RNA molecules — chemical cousins to DNA that can both store and transmit genetic information — might have assembled themselves out of simpler units, a process that many scientists believe led to the first living things.

    Unfortunately, he had a problem. At a chemical level, a deep bias permeates all of biology. The molecules that make up DNA and other nucleic acids such as RNA have an inherent “handedness.” These molecules can exist in two mirror image forms, but only the right-handed version is found in living organisms. Handedness serves an essential function in living beings; many of the chemical reactions that drive our cells only work with molecules of the correct handedness. But the pre-biological building blocks of life didn’t exhibit such an overwhelming bias. Some were left-handed and some right. So how did right-handed RNA emerge from a mix of molecules?

    Joyce was able to build RNA out of right-handed building blocks, as others had done before him. But when he added in left-handed molecules, mimicking the conditions on the early Earth, everything came to a halt. “Our paper said if you have [both] forms in the same place at the same time, you can’t even get started,” Joyce said.

    His findings, published in Nature in 1984, suggested that in order for life to emerge, something first had to crack the symmetry between left-handed and right-handed molecules, an event biochemists call “breaking the mirror.” Since then, scientists have largely focused their search for the origin of life’s handedness in the prebiotic worlds of physics and chemistry, not biology.

    Olena Shmahalo / Quanta Magazine
    Many molecules come in mirror-image forms, known as left-handed and right-handed. A chemical process will create both forms of a given molecule, but a biological processes will produce just one.

    Three decades later, Joyce’s latest research has shown that perhaps life came first after all. Joyce, now at the Scripps Research Institute in La Jolla, Calif., and Jonathan Sczepanski, a postdoctoral researcher, created an RNA enzyme — a substance that copies RNA — that can function in a soup of left- and right-handed building blocks, providing a potential mechanism for how some of the first biological molecules might have evolved in a symmetrical world. The new experiment, published in the November 20 issue of Nature, is reinvigorating the discussion over how life first arose. “They have really opened up a new realm of possible roads,” said Niles Lehman, a biochemist at Portland State University in Oregon who wasn’t involved in the study.

    Even more intriguing, Joyce and Sczepanski’s enzyme works differently from other RNA-copying molecules, a discovery that may have profound implications for how life originated. The enzyme is much more efficient and flexible than other RNA-based enzymes developed to date, and it may provide the key to Joyce’s ultimate goal — making life from scratch.

    A Crack in the Mirror

    Louis Pasteur, the famous 19th-century French chemist, was the first to describe chemical handedness, or “chirality.” He was puzzled by the fact that crystals derived from the dregs of wine twisted light in a specific direction, but the same crystal synthesized in the lab did not. Examining the crystals under a microscope, he discovered that the synthetic chemical came in two mirror-image forms, which canceled out the polarizing effect. The crystal derived from wine had only one.

    Scientists later discovered that this bias encompasses the entire living world. Synthetic chemical processes will generate both left- and right-handed molecules. But when nature makes a molecule, the product is either left- or right-handed. For example, all amino acids that are used to make proteins twist light to the left.

    Indeed, chirality is an essential component of biochemistry. “It provides a form of molecular recognition,” said Donna Blackmond, a chemical engineer at Scripps and a colleague of Joyce’s. The chirality of a molecule affects how it interacts with other components of the cell. Molecular locks can only be opened with a key of the correct handedness.

    Some scientists look to the heavens to explain how this biological bias first arose. Some meteorites show a slight predominance of left-handed amino acids, the building blocks of proteins, suggesting that the influence came from outer space. An alternative cosmic origin story proposes that circularly polarized light coming from a supernova triggered a bias. In addition, radioactive decays produce electrons that are slightly more likely to be left-handed. Such electrons raining down on Earth’s surface might have changed its early chemistry.

    Yet most biologists and chemists are skeptical of these astrophysical theories. The bias they create is just too minute. The theories create “a beautiful union between life and nonlife,” said Marcelo Gleiser, a theoretical physicist at Dartmouth College. “But the problem is that those interactions are very weak and short-range.” According to Joyce, the effect of these physical forces would be lost in the noise of chemical reactions. “Such a small asymmetry in the universe is not enough to move the needle,” he said.

    Biochemists have tended to favor an alternative proposal, that a chance occurrence of prebiotic chemistry triggered an initial disequilibrium. Perhaps a slight excess of right-handed nucleotides was trapped and amplified in a shallow pool or some other prebiotic test tube. Eventually the bias reached a tipping point, breaking the chemical mirror and setting the stage for the emergence of life. Blackmond has done extensive work showing how to transform a small asymmetry to a nearly complete one using purely physical and chemical means.

    Shaking Both Hands

    When Joyce entered the field 30 years ago, researchers were already trying to test some of the astrophysical theories. But Joyce was skeptical. “I thought, why are you trying so hard to find a universal explanation when it’s probably chance?” he said.
    Gerald Joyce (right), a biochemist at the Scripps Research Institute, and postdoc Jonathan Sczepanski created an RNA enzyme that can replicate in an entirely new way.

    Gerald Joyce (right), a biochemist at the Scripps Research Institute, and postdoc Jonathan Sczepanski created an RNA enzyme that can replicate in an entirely new way.
    Courtesy of The Scripps Research Institute.

    Around the same time, scientists were trying to figure out how the building blocks of life — amino acids and nucleic acids — could have spontaneously formed into more complex molecules such as proteins, DNA and RNA. Joyce thought that this assembly process might generate a crack in the mirror. A reaction that selectively plucked right-handed building blocks from the primordial soup would quickly start to create only right-handed molecules, just as a machine that selects only red or only blue Legos from a mixed box would create single-colored towers.

    Such a process would simultaneously solve two problems in the origins of life: It would create complex biological molecules while breaking the mirror. Joyce’s experiment in the 1980s set out to test that idea, but its failure called into question how right-handed RNA molecules could form from the ingredients of the primordial soup. “It was a mess,” Joyce said. “The left-handed building block poisons the growing chain.”

    The findings were particularly problematic for the nascent “RNA world” theory, which proposed that life began with an RNA molecule capable of replicating itself. RNA is the best candidate for the first biological molecule because it shares characteristics of both DNA and proteins. Like DNA, it carries information in its sequence of bases. And like an enzyme, it can catalyze chemical reactions. (RNA enzymes are known as ribozymes.)

    But if a ribozyme that copies RNA can’t function in a chemically symmetrical world, how could RNA-based life have emerged? “It’s kind of a showstopper,” said Peter Unrau, a biochemist at Simon Fraser University in Canada. In the decades since Joyce’s 1984 experiment, scientists have proposed myriad ways around the problem, from physical and chemical theories to RNA precursors that lack chirality.

    Given the known limitations, Joyce began to focus on creating a simple ribozyme that could copy RNA when only right-handed blocks were around. His group had some success, but none that fulfilled the requirements of the RNA world theory.

    So last year, Joyce and Sczepanski decided to start from scratch. They unleashed a pool of random right-handed RNA molecules and let them react in a test tube with left-handed building blocks. They hoped that within that random pool of RNA molecules was a ribozyme capable of stringing the building blocks together. They then isolated the best candidates — ribozymes that could copy RNA of the opposite handedness — replicated them, and subjected the new pool to the same trial over and over again.

    In just a few short months, they had a surprisingly effective ribozyme. The right-handed version binds to a left-handed RNA template and produces a left-handed copy. The left-handed copy can then go on to produce a right-handed version. “It’s amazing what they did,” said John Chaput, a biochemist at Arizona State University in Tempe. “It really does get to the heart of the question of the origins of chirality and provides some solid evidence to move things forward.”

    Perhaps even more exciting is how well the enzyme works. Other ribozymes created to date are too finicky to have spawned life; they replicate only certain RNA sequences, like soil that will grow potatoes but not carrots or peas. But Joyce’s ribozyme could produce a range of sequences — including its own. And it’s still getting better. The ribozyme in the paper emerged after just 16 rounds of evolution, a shockingly short run for this kind of experiment. Further rounds of evolution have already boosted its abilities, though these findings are not yet published. “The beautiful thing is that this is still a young enzyme,” Lehman said. “There’s lots of room for improvement.”

    The new ribozyme nearly fulfills the most basic properties of life — the ability to replicate and to evolve.

    The reason the new ribozyme works so well lies in the unusual way it operates. A regular ribozyme binds to its target according to its sequence of letters, like two sides of a zipper coming together. Sometimes it works too well, and the targets get stuck. This kind of binding only works with two molecules of the same handedness, which means Joyce’s ribozyme can’t bind this way.

    Instead, it binds based on the molecule’s shape rather than its sequence, an approach that turns out to be much more flexible. “They found something completely novel,” Lehman said. “It goes to show there’s a lot out there we don’t know.”

    Scientists now have an enzyme that doesn’t need a chiral world. Researchers, including Joyce himself, are still trying to understand the implications. The findings open the possibility that chirality emerged after life first evolved. “Maybe we didn’t need to break symmetry,” said Blackmond.

    Jack Szostak, a biochemist at Harvard University and one of Joyce’s collaborators, is excited by the findings, particularly because the ribozyme is so much more flexible than earlier versions. But, he said, “I am skeptical that life began in this way.” Szostak argues that this scenario would require both left-handed and right-handed RNA enzymes to have emerged at the same time and in the same place, which would be highly unlikely.

    Right-Handed Reign

    If chirality emerged sometime after the origins of life, the question remains: Why did right-handed RNA win? Left- and right-handed molecules have chemically identical properties, so there’s no obvious reason for one to triumph.

    Joyce and others suspect it’s simply chance. Say a ribozyme capable of transforming a pool of mixed nucleic acids into left- and right-handed RNAs appeared on the early Earth. It would produce two distinct groups, lefties and righties, which in turn might have functioned like competing populations. “If the right hand stumbles on useful mutations and runs away with the game, then the other side of the mirror can go dark,” Joyce said. For example, the right-handed group of RNAs might have developed some kind of competitive advantage, such as producing proteins, eventually overtaking the left-handed group and generating the bias we see today.

    There is only one way to truly determine whether one hand is superior: Build life forms that twist in each direction and evaluate them side by side. George Church and collaborators at Harvard are aiming to do just that. If they can make mirror versions of all the cells’ parts, they can construct synthetic cells and compare otherwise identical left- and right-handed versions of life.

    To create mirror-image RNAs, Church and his collaborators first need to make mirror enzymes capable of stitching together mirror building blocks. Michael Kay’s team at the University of Utah has almost finished developing a method for chemically synthesizing an ordinary version of one such enzyme. Once completed, the two teams will apply the same approach to make a mirror enzyme capable of assembling mirror RNAs. Church and others are also building tools to detect mirror life, which could prove important when searching for signs of life on other planets.

    Joyce remains interested in making life from scratch. Everything else, including the chirality problem, is just a hurdle toward that larger prize, he said.

    The new ribozyme may provide the best shot yet. It nearly fulfills the most basic properties of life — the ability to replicate and to evolve. “They went so far as to show the mirror image can copy itself,” Chaput said. “That gets very close to replication.” The next step will be to make that happen iteratively. “If you look in the mirror, make a copy, then put yourself in the mirror, and make a copy of the person in the mirror, then you have replication,” Chaput said.

    That iterative process opens the possibility for evolution, as mistakes made during copying will allow the molecule to evolve new traits. “The real key to all of it has been setting up a system in the lab capable of evolution on its own,” Unrau said. “Jerry is close.”

    See the full article here.

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    Formerly known as Simons Science News, Quanta Magazine is an editorially independent online publication launched by the Simons Foundation to enhance public understanding of science. Why Quanta? Albert Einstein called photons “quanta of light.” Our goal is to “illuminate science.” At Quanta Magazine, scientific accuracy is every bit as important as telling a good story. All of our articles are meticulously researched, reported, edited, copy-edited and fact-checked.

  • richardmitnick 11:39 am on September 16, 2014 Permalink | Reply
    Tags: , , Genetics,   

    From M.I.T.: “Neuroscientists identify key role of language gene” 

    MIT News

    September 15, 2014
    Anne Trafton | MIT News Office

    Neuroscientists have found that a gene mutation that arose more than half a million years ago may be key to humans’ unique ability to produce and understand speech.


    Researchers from MIT and several European universities have shown that the human version of a gene called Foxp2 makes it easier to transform new experiences into routine procedures. When they engineered mice to express humanized Foxp2, the mice learned to run a maze much more quickly than normal mice.

    The findings suggest that Foxp2 may help humans with a key component of learning language — transforming experiences, such as hearing the word “glass” when we are shown a glass of water, into a nearly automatic association of that word with objects that look and function like glasses, says Ann Graybiel, an MIT Institute Professor, member of MIT’s McGovern Institute for Brain Research, and a senior author of the study.

    “This really is an important brick in the wall saying that the form of the gene that allowed us to speak may have something to do with a special kind of learning, which takes us from having to make conscious associations in order to act to a nearly automatic-pilot way of acting based on the cues around us,” Graybiel says.

    Wolfgang Enard, a professor of anthropology and human genetics at Ludwig-Maximilians University in Germany, is also a senior author of the study, which appears in the Proceedings of the National Academy of Sciences this week. The paper’s lead authors are Christiane Schreiweis, a former visiting graduate student at MIT, and Ulrich Bornschein of the Max Planck Institute for Evolutionary Anthropology in Germany.

    All animal species communicate with each other, but humans have a unique ability to generate and comprehend language. Foxp2 is one of several genes that scientists believe may have contributed to the development of these linguistic skills. The gene was first identified in a group of family members who had severe difficulties in speaking and understanding speech, and who were found to carry a mutated version of the Foxp2 gene.

    In 2009, Svante Pääbo, director of the Max Planck Institute for Evolutionary Anthropology, and his team engineered mice to express the human form of the Foxp2 gene, which encodes a protein that differs from the mouse version by only two amino acids. His team found that these mice had longer dendrites — the slender extensions that neurons use to communicate with each other — in the striatum, a part of the brain implicated in habit formation. They were also better at forming new synapses, or connections between neurons.

    Pääbo, who is also an author of the new PNAS paper, and Enard enlisted Graybiel, an expert in the striatum, to help study the behavioral effects of replacing Foxp2. They found that the mice with humanized Foxp2 were better at learning to run a T-shaped maze, in which the mice must decide whether to turn left or right at a T-shaped junction, based on the texture of the maze floor, to earn a food reward.

    The first phase of this type of learning requires using declarative memory, or memory for events and places. Over time, these memory cues become embedded as habits and are encoded through procedural memory — the type of memory necessary for routine tasks, such as driving to work every day or hitting a tennis forehand after thousands of practice strokes.

    Using another type of maze called a cross-maze, Schreiweis and her MIT colleagues were able to test the mice’s ability in each of type of memory alone, as well as the interaction of the two types. They found that the mice with humanized Foxp2 performed the same as normal mice when just one type of memory was needed, but their performance was superior when the learning task required them to convert declarative memories into habitual routines. The key finding was therefore that the humanized Foxp2 gene makes it easier to turn mindful actions into behavioral routines.

    The protein produced by Foxp2 is a transcription factor, meaning that it turns other genes on and off. In this study, the researchers found that Foxp2 appears to turn on genes involved in the regulation of synaptic connections between neurons. They also found enhanced dopamine activity in a part of the striatum that is involved in forming procedures. In addition, the neurons of some striatal regions could be turned off for longer periods in response to prolonged activation — a phenomenon known as long-term depression, which is necessary for learning new tasks and forming memories.

    Together, these changes help to “tune” the brain differently to adapt it to speech and language acquisition, the researchers believe. They are now further investigating how Foxp2 may interact with other genes to produce its effects on learning and language.

    This study “provides new ways to think about the evolution of Foxp2 function in the brain,” says Genevieve Konopka, an assistant professor of neuroscience at the University of Texas Southwestern Medical Center who was not involved in the research. “It suggests that human Foxp2 facilitates learning that has been conducive for the emergence of speech and language in humans. The observed differences in dopamine levels and long-term depression in a region-specific manner are also striking and begin to provide mechanistic details of how the molecular evolution of one gene might lead to alterations in behavior.”

    The research was funded by the Nancy Lurie Marks Family Foundation, the Simons Foundation Autism Research Initiative, the National Institutes of Health, the Wellcome Trust, the Fondation pour la Recherche Médicale, and the Max Planck Society.

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  • richardmitnick 9:43 am on September 14, 2014 Permalink | Reply
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    From M.I.T Tech Review: “Gene-Silencing Drugs Finally Show Promise” 

    MIT Technology Review
    M.I.T Technology Review

    September 14, 2014
    Kevin Bullis

    After more than a decade of disappointment, a startup leads the development of a powerful new class of drugs based on a Nobel-winning idea.

    The disease starts with a feeling of increased clumsiness. Spilling a cup of coffee. Stumbling on the stairs. Having accidents that are easy to dismiss—everyone trips now and then.

    But it inevitably gets worse. Known as familial amyloid polyneuropathy, or FAP, it can go misdiagnosed for years as patients lose the ability to walk or perform delicate tasks with their hands. Most patients die within 10 to 15 years of the first symptoms.

    There is no cure. The disease is caused by malformed proteins produced in the liver, so one treatment is a liver transplant. But few patients can get one—and it only slows the disease down.

    Now, after years of false starts and disappointment, it looks like an audacious idea for helping these patients finally could work.

    In 1998, researchers at the Carnegie Institution and the University of Massachusetts made a surprising discovery about how cells regulate which proteins they produce. They found that certain kinds of RNA—which is what DNA makes to create proteins—can turn off specific genes. The finding, called RNA interference (RNAi), was exciting because it suggested a way to shut down the production of any protein in the body, including those connected with diseases that couldn’t be touched with ordinary drugs. It was so promising that its discoverers won the Nobel Prize just eight years later.

    Inspired by the discovery, another group of researchers—including the former thesis supervisor of one of the Nobel laureates—founded Alnylam in Cambridge, Massachusetts, in 2002. Their goal: fight diseases like FAP by using RNAi to eliminate bad proteins (see “The Prize of RNAi” and “Prescription RNA”). Never mind that no one knew how to make a drug that could trigger RNAi. In fact, that challenge would bedevil the researchers for the better part of a decade. Along the way, the company lost the support of major drug companies that had signed on in a first wave of enthusiasm. At one point the idea of RNAi therapy was on the verge of being discredited.

    But now Alnylam is testing a drug to treat FAP in advanced human trials. It’s the last hurdle before the company will seek regulatory approval to put the drug on the market. Although it’s too early to tell how well the drug will alleviate symptoms, it’s doing what the researchers hoped it would: it can decrease the production of the protein that causes FAP by more than 80 percent.

    This could be just the beginning for RNAi. Alnylam has more than 11 drugs, including ones for hemophilia, hepatitis B, and even high cholesterol, in its development pipeline, and has three in human trials —progress that led the pharmaceutical company Sanofi to make a $700 million investment in the company last winter. Last month, the pharmaceutical giant Roche, an early Alnylam supporter that had given up on RNAi, reversed its opinion of the technology as well, announcing a $450 million deal to acquire the RNAi startup Santaris. All told, there are about 15 RNAi-based drugs in clinical trials from several research groups and companies.

    “The world went from believing RNAi would change everything to thinking it wouldn’t work, to now thinking it will,” says Robert Langer, a professor at MIT, and one of Alnylam’s advisors.

    Delivering Drugs

    Alnylam started with high hopes. Its founders, among them the Nobel laureate and MIT biologist Philip Sharp, had solved one of the biggest challenges facing the idea of RNAi therapies. When RNAi was discovered, the process was triggered by introducing a type of RNA, called double stranded RNA, into cells. This worked well in worms and fruit flies. But the immune system in mammals reacted violently to the RNA, causing cells to die and making the approach useless except as a research tool. The Alnylam founders figured out that shorter strands, called siRNA, could slip into mammalian cells without triggering an immune reaction, suggesting a way around this problem.

    Yet another huge problem remained. RNA interference depends upon delivering RNA to cells, tricking the cells into allowing it through the protective cell membrane, and then getting the cells to incorporate it into molecular machinery that regulates proteins. Scientists could do this in petri dishes but not in animals.

    Alnylam looked everywhere for solutions, scouring the scientific literature, collaborating with other companies, considering novel approaches of its own. It focused on two options. One was encasing RNA in bubbles of fat-like nanoparticles of lipids. They are made with the same materials that make up cell membranes—the thought was that the cell would respond well to the familiar substance. The other approach was attaching a molecule to the RNA that cells like to ingest, tricking the cell into eating it.

    And both approaches worked, sort of. Researchers were able to block protein production in lab animals. But getting the delivery system right wasn’t easy. The early mechanisms were too toxic at the doses required to be used as drugs.

    As a result, delivering RNA through the bloodstream like a conventional drug seemed a far-off prospect. The company tried a shortcut of injecting chemically modified RNA directly into diseased tissue —for example, into the retina to treat eye diseases. That approach even got to clinical trials. But it was shelved because it didn’t perform as well as up-and-coming drugs from other companies.

    By 2010, some of the major drug companies that were working with and investing in Alnylam lost patience. Novartis decided not to extend a partnership with Alnylam; Roche gave up on RNAi altogether. Alnylam laid off about a quarter of its workers, and by mid-2011, its stock price had plunged by 80 percent from its peak.

    But Alnylam and partner companies, notably the Canadian startup Tekmira, were making steady progress in the lab. Researchers identified one part of the lipid nanoparticles that was keeping them from delivering its cargo of RNA to the right part of a cell. That was “the real eureka moment,” says Rachel Meyers, Alnylam’s vice president of research. Better nanoparticles improved the potency of a drug a hundredfold and its safety by about five times, clearing the way for clinical trials for FAP—a crucial event that kept the company alive.

    Even with that progress, Alnylam needed more. The nanoparticle delivery mechanism is costly to make and requires frequent visits to the hospital for hour-long IV infusions—something patients desperate to stay alive will put up with, but likely not millions of people with high cholesterol.

    So Alnylam turned to its second delivery approach—attaching molecules to RNA to trick cells into ingesting it. Researchers found just the right inducement—attaching a type of sugar molecule. This approach allows for the drug to be administered with a simple injection that patients could give themselves at home.

    In addition to being easier to administer, the new sugar-based drugs are potentially cheaper to make. The combination of low cost and ease-of-use is allowing Alnylam to go after more common diseases—not just the rare ones that patients will go to great lengths to treat. “Because we’ve made incredible improvements in the delivery strategy,” Meyers says, “we can now go after big diseases where we can treat millions of patients potentially.”

    The Next Frontier

    In a sixth-floor lab on the MIT campus, postdoctoral researcher James Dahlman takes down boxes from a high shelf. They contain hundreds of vials, each containing a unique type of nanoparticle that Dahlman synthesized painstakingly, one at a time. “It turns out we have a robot in the lab that can do that,” he says. “But I didn’t know about it at the time.”

    Dahlman doesn’t work for Alnylam; he had been searching for the next great delivery mechanism, one that could greatly expand the diseases that can be treated by RNAi. Some of the materials look like clear liquids. Some are waxy, some like salt crystals. He points to a gap in the rows of vials, where a vial is conspicuously missing. “That’s the one that worked. That’s the miracle material,” he says.

    For all of their benefits, the drug delivery mechanisms Alnylam uses have one flaw—they’re effective only for delivering drugs to liver cells. For a number of reasons, the liver is a relatively easy target—that’s where all kinds of nanoparticles tend to end up. Alnylam sees the potential for billions of dollars in revenue from liver-related diseases. Yet most diseases involve other tissues in the body.

    Dahlman and his colleagues at MIT are some of the leaders in the next generation of RNAi delivery—targeting delivery to places throughout the body. Last month, in two separate articles, they published the results of studies showing that Dahlman’s new nanoparticles are a powerful way to deliver RNAi to blood vessel cells, which are associated with a wide variety of diseases. The studies showed that the method could be used to reduce tumor growth in lung cancer, for example.

    Treating cancer is one area where RNAi’s particular advantages are expected to shine. Conventional chemotherapy affects more than just the target cancer cells—it also hurts healthy tissue, which is why it makes people feel miserable. But RNAi can be extremely precise, potentially shutting down only proteins found in cancer cells. And Dahlman’s latest delivery system makes it possible to simultaneously target up to 10 proteins at once, which could make cancer treatments far more effective. Lab work like this is far from fruition, but if it maintains its momentum, the drugs currently in clinical trials could represent just a small portion of the benefits of the discovery of RNAi.

    See the full article here.

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  • richardmitnick 7:37 am on September 10, 2014 Permalink | Reply
    Tags: , , Genetics   

    From Astrobiology: “A single evolutionary road may lead to Rome” 

    Astrobiology Magazine

    Astrobiology Magazine

    Sep 10, 2014
    Contact(s): Layne Cameron Media Communications office: (517) 353-8819 cell: (765) 748-4827 Layne.Cameron@cabs.msu.edu , Jason Gallant Zoology office: (517) 884-7756 jgallant@msu.edu, Michigan State University

    A well-known biologist once theorized that many roads led to Rome when it comes to two distantly related organisms evolving a similar trait. A new paper, published in Nature Communications, suggests that when it comes to evolving some traits – especially simple ones – there may be a shared gene, one road, that’s the source.

    Jason Gallant, MSU zoologist, shows that a single evolutionary road may lead to Rome. Photo by G.L. Kohuth – See more at: http://www.astrobio.net/topic/origins/origin-and-evolution-of-life/single-evolutionary-road-may-lead-rome/#sthash.d9t39bd2.dpuf

    Jason Gallant, MSU zoologist and the paper’s first author, focused on butterflies to illustrate his metaphorical roadmap on evolutionary traits. Butterfly wings are important biological models. While some butterflies are poisonous and notify their predators via colorful wing markings, others are nontoxic but have evolved similar color patterns to avoid being eaten.

    Many scientists, including the famed Ernst Mayr, favored the “many roads” theory. This was largely attributed to being unable to identify a shared gene for such traits. Gallant, Sean Mullen, co-author and Boston University biologist, and their collaborators, however, were able to pinpoint the single gene responsible for two different families of butterflies’ flashy markings.

    The North American and South American species last had a common ancestor more than 65 million years ago. So, rather than evolve these traits independently using two unique mechanisms, the genetic control of particular butterfly markings can be traced to a single gene present in their ancient ancestors, said Gallant, who also teamed with Arnaud Martin and Bob Reed from Cornell University, and Marcus Kronforst from the University of Chicago.

    “This result represents the culmination of a decade’s worth of effort, but we identified the mechanism for a single aspect of wing patterns in a lineage,” Gallant said. “Is this the rule or the exception? For simple traits, it’s beginning to look like it could be the rule. The jury is still out on complicated traits, but there may be fewer roads leading to Rome than we once thought.”

    The decade-long journey began as a butterfly mapping study and later involved the 30,000 genes that comprise white admiral butterflies and red-spotted purple butterflies in North America. They are the same species of butterflies, but to a common observer, they look completely unrelated.

    Jason Gallant, MSU zoologist, studied butterflies to illustrate his metaphorical roadmap on evolutionary traits. Photo by G.L. Kohuth

    In the southern United States, the red-spotted purples [Limenitis arthemis] have dark-blue wings that mimic the poisonous pipevine swallowtail. The white admirals [also Limenitis arthemis], with distinctive white bands on their wings, reside in northern climes where the swallowtail is not found. A hybrid of the two can be found in a region near Pennsylvania.

    Red Spotted Purple

    White admiral

    Out of the 30,000 genes, Gallant, Mullen and their team narrowed the candidates to three. In one of these genes, WntA, they discovered the presence of a retrotransposon, a DNA virus of sorts, which appears to cause the deviations in wing pattern.

    “It’s the same type of DNA ‘virus’ that causes random-colored kernels in Indian corn,” Gallant said. “It was present in 100 percent of the red-spotted purples, 50 percent of the hybrids and zero percent of the white admirals; I’ve never seen such clean data like this – ever.”

    For comparison, a different species of South American butterflies, studied by researchers from Cornell and the University of Chicago, were folded into the experiment. This species is separated by a mountain range rather than a continent, but the genetic patterns were the same. The group with dark wing markings had a deletion in the WntA gene in the same spot that the retrotransposon occurred in the North American butterflies.

    When asked to comment on the significance of the work, Mullen stated the main goal of evolutionary biology is to understand the origin and maintenance of biodiversity. Within this context, a major unanswered question is whether or not evolution is predictable, and, if so, over what evolutionary time scales?

    “We addressed this question by identifying the specific genetic changes responsible for the repeated evolution of similar color pattern traits in two butterfly lineages that last shared a common ancestor some 65 million years ago,” he said. “Surprisingly, we found that changes in the expression of the same gene during development were responsible in both cases. This result implies an unprecedented level of predictability in the evolutionary process over deep time.”

    Since this evolutionary trait was triggered, perhaps somewhat accidentally, it stirs questions as to what other changes are taking place before our eyes.

    “Copying errors and genomic viruses directly lead to the wing patterns of these beautiful butterflies,” Gallant said. “It’s these accidents that allow the evolutionary process to move forward. When I look over a field of butterflies, it makes me wonder what types of ‘mistakes’ are happening right now that may lead to important evolutionary changes years from now? What evolutionary processes will we someday be able to predict?”

    See the full article here.


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  • richardmitnick 8:06 pm on August 27, 2014 Permalink | Reply
    Tags: , , Genetics, ,   

    From Berkeley Lab: “Encyclopedia of How Genomes Function Gets Much Bigger” 

    Berkeley Logo

    Berkeley Lab

    August 27, 2014
    Dan Krotz 510-486-4019

    A big step in understanding the mysteries of the human genome was unveiled today in the form of three analyses that provide the most detailed comparison yet of how the genomes of the fruit fly, roundworm, and human function.

    The research, appearing August 28 in in the journal Nature, compares how the information encoded in the three species’ genomes is “read out,” and how their DNA and proteins are organized into chromosomes.

    The results add billions of entries to a publicly available archive of functional genomic data. Scientists can use this resource to discover common features that apply to all organisms. These fundamental principles will likely offer insights into how the information in the human genome regulates development, and how it is responsible for diseases.

    Berkeley Lab scientists contributed to an NHGRI effort that provides the most detailed comparison yet of how the genomes of the fruit fly, roundworm, and human function. (Credit: Darryl Leja, NHGRI)

    The analyses were conducted by two consortia of scientists that include researchers from the Department of Energy’s Lawrence Berkeley National Laboratory (Berkeley Lab). Both efforts were funded by the National Institutes of Health’s National Human Genome Research Institute.

    One of the consortiums, the “model organism Encyclopedia of DNA Elements” (modENCODE) project, catalogued the functional genomic elements in the fruit fly and roundworm. Susan Celniker and Gary Karpen of Berkeley Lab’s Life Sciences Division led two fruit fly research groups in this consortium. Ben Brown, also with the Life Sciences Division, participated in another consortium, ENCODE, to identify the functional elements in the human genome.

    The consortia are addressing one of the big questions in biology today: now that the human genome and many other genomes have been sequenced, how does the information encoded in an organism’s genome make an organism what it is? To find out, scientists have for the past several years studied the genomes of model organisms such as the fruit fly and roundworm, which are smaller than our genome, yet have many genes and biological pathways in common with humans. This research has led to a better understanding of human gene function, development, and disease.

    Comparing Transcriptomes

    In all organisms, the information encoded in genomes is transcribed into RNA molecules that are either translated into proteins, or utilized to perform functions in the cell. The collection of RNA molecules expressed in a cell is known as its transcriptome, which can be thought of as the “read out” of the genome.

    In the research announced today, dozens of scientists from several institutions looked for similarities and differences in the transcriptomes of human, roundworm, and fruit fly. They used deep sequencing technology and bioinformatics to generate large amounts of matched RNA-sequencing data for the three species. This involved 575 experiments that produced more than 67 billion sequence reads.

    A team led by Celniker, with help from Brown and scientists from several other labs, conducted the fruit fly portion of this research. They mapped the organism’s transcriptome at 30 time points of its development. They also explored how environmental perturbations such as heavy metals, herbicides, caffeine, alcohol and temperature affect the fly’s transcriptome. The result is the finest time-resolution analysis of the fly genome’s “read out” to date—and a mountain of new data.

    “We went from two billion reads in research we published in 2011, to 20 billion reads today,” says Celniker. “As a result, we found that the transcriptome is much more extensive and complex than previously thought. It has more long non-coding RNAs and more promoters.”

    When the scientists compared transcriptome data from all three species, they discovered 16 gene-expression modules corresponding to processes such as transcription and cell division that are conserved in the three animals. They also found a similar pattern of gene expression at an early stage of embryonic development in all three organisms.

    This work is described in a Nature article entitled “Comparative analysis of the transcriptome across distant species.”

    Comparing chromatin

    Another group, also consisting of dozens of scientists from several institutions, analyzed chromatin, which is the combination of DNA and proteins that organize an organism’s genome into chromosomes. Chromatin influences nearly every aspect of genome function.

    Karpen led the fruit fly portion of this work, with Harvard Medical School’s Peter Park contributing on the bioinformatics side, and scientists from several other labs also participating. The team mapped the distribution of chromatin proteins in the fruit fly genome. They also learned how chemical modifications to chromatin proteins impact genome functions.

    Their results were compared with results from human and roundworm chromatin research. In all, the group generated 800 new chromatin datasets from different cell lines and developmental stages of the three species, bringing the total number of datasets to more than 1400. These datasets are presented in a Nature article entitled “Comparative analysis of metazoan chromatin organization.”

    Here again, the scientists found many conserved chromatin features among the three organisms. They also found significant differences, such as in the composition and locations of repressive chromatin.

    But perhaps the biggest scientific dividend is the data itself.

    “We found many insights that need follow-up,” says Karpen. “And we’ve also greatly increased the amount of data that others can access. These datasets and analyses will provide a rich resource for comparative and species-specific investigations of how genomes, including the human genome, function.”

    See the full article here.

    A U.S. Department of Energy National Laboratory Operated by the University of California

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