The Center for Advanced Biotechnology & Medicine

A team of scientists dedicated to pinpointing the primordial origins of metabolism -- a set of core chemical reactions that first powered life on Earth -- has identified part of a protein that could provide scientists clues to detecting planets on the verge of producing life. A team of Rutgers scientists dedicated to pinpointing the primordial origins of metabolism -- a set of core chemical reactions that first powered life on Earth -- has identified part of a protein that could provide scientists clues to detecting planets on the verge of producing life. The research, published in Science Advances, has important implications in the search for extraterrestrial life because it gives researchers a new clue to look for, said Vikas Nanda, a researcher at the Center for Advanced Biotechnology and Medicine (CABM) at Rutgers. Based on laboratory studies, Rutgers scientists say one of the most likely chemical candidates that kickstarted life was a simple peptide with two nickel atoms they are calling "Nickelback" not because it has anything to do with the Canadian rock band, but because its backbone nitrogen atoms bond two critical nickel atoms. A peptide is a constituent of a protein made up of a few elemental building blocks known as amino acids. "Scientists believe that sometime between 3.5 and 3.8 billion years ago there was a tipping point, something that kickstarted the change from prebiotic chemistry -- molecules before life -- to living, biological systems," Nanda said. "We believe the change was sparked by a few small precursor proteins that performed key steps in an ancient metabolic reaction. And we think we've found one of these 'pioneer peptides'." The scientists conducting the study are part of a Rutgers-led team called Evolution of Nanomachines in Geospheres and Microbial Ancestors (ENIGMA), which is part of the Astrobiology program at NASA. The researchers are seeking to understand how proteins evolved to become the predominant catalyst of life on Earth. When scouring the universe with telescopes and probes for signs of past, present or emerging life, NASA scientists look for specific "biosignatures" known to be harbingers of life. Peptides like nickelback could become the latest biosignature employed by NASA to detect planets on the verge of producing life, Nanda said. An original instigating chemical, the researchers reasoned, would need to be simple enough to be able to assemble spontaneously in a prebiotic soup. But it would have to be sufficiently chemically active to possess the potential to take energy from the environment to drive a biochemical process. To do so, the researchers adopted a "reductionist" approach: They started by examining existing contemporary proteins known to be associated with metabolic processes. Knowing the proteins were too complex to have emerged early on, they pared them down to their basic structure. After sequences of experiments, researchers concluded the best candidate was Nickelback. The peptide is made of 13 amino acids and binds two nickel ions. Nickel, they reasoned, was an abundant metal in early oceans. When bound to the peptide, the nickel atoms become potent catalysts, attracting additional protons and electrons and producing hydrogen gas. Hydrogen, the researchers reasoned, was also more abundant on early Earth and would have been a critical source of energy to power metabolism. "This is important because, while there are many theories about the origins of life, there are very few actual laboratory tests of these ideas," Nanda said. "This work shows that, not only are simple protein metabolic enzymes possible, but that they are very stable and very active -- making them a plausible starting point for life."

Early exposure to antibiotics kills healthy bacteria in the digestive tract and can cause asthma and allergies, a new study demonstrates. Early exposure to antibiotics kills healthy bacteria in the digestive tract and can cause asthma and allergies, a new study demonstrates. The study, published in Mucosal Immunology, has provided the strongest evidence so far that the long-observed connection between antibiotic exposure in early childhood and later development of asthma and allergies is causal. "The practical implication is simple: Avoid antibiotic use in young children whenever you can because it may elevate the risk of significant, long-term problems with allergy and/or asthma," said senior author Martin Blaser, director of the Center for Advanced Biotechnology and Medicine at Rutgers. In the study, the researchers, who came from Rutgers, New York University and the University of Zurich, noted that antibiotics, "among the most used medications in children, affect gut microbiome communities and metabolic functions. These changes in microbiota structure can impact host immunity." In the first part of the experiment, five-day-old mice received water, azithromycin or amoxicillin. After the mice matured, researchers exposed them to a common allergen derived from house dust mites. Mice that had received either of the antibiotics, especially azithromycin, exhibited elevated rates of immune responses -- i.e., allergies. The second and third parts of the experiment tested the hypothesis that early exposure to antibiotics (but not later exposure) causes allergies and asthma by killing some healthy gut bacteria that support proper immune system development. Lead author Timothy Borbet first transferred bacteria-rich fecal samples from the first set of mice to a second set of adult mice with no previous exposure to any bacteria or germs. Some received samples from mice given azithromycin or amoxicillin in infancy. Others received normal samples from mice that had received water. Mice that received antibiotic-altered samples were no more likely than other mice to develop immune responses to house dust mites, just as people who receive antibiotics in adulthood are no more likely to develop asthma or allergies than those who don't. Things were different, however, for the next generation. Offspring of mice that received antibiotic-altered samples reacted more to house dust mites than those whose parents received samples unaltered by antibiotics, just as mice that originally received antibiotics as babies reacted more to the allergen than those that received water. "This was a carefully controlled experiment," said Blaser. "The only variable in the first part was antibiotic exposure. The only variable in the second two parts was whether the mixture of gut bacteria had been affected by antibiotics. Everything else about the mice was identical. Blaser added that "these experiments provide strong evidence that antibiotics cause unwanted immune responses to develop via their effect on gut bacteria, but only if gut bacteria are altered in early childhood."

Scientists have determined the molecular structure of HIV Pol, a protein that plays a key role in the late stages of HIV replication, or the process through which the virus propagates itself and spreads through the body. Importantly, determining the molecule's structure helps answer longstanding questions about how the protein breaks itself apart to advance the replication process. The discovery reveals a new vulnerability in the virus that could be targeted with drugs. Understanding how HIV replicates within cells is key for developing new therapies that could help nearly 40 million people living with HIV globally. Now, a team of scientists from the Salk Institute and Rutgers University have for the first time determined the molecular structure of HIV Pol, a protein that plays a key role in the late stages of HIV replication, or the process through which the virus propagates itself and spreads through the body. Importantly, determining the molecule's structure helps answer longstanding questions about how the protein breaks itself apart to advance the replication process. The discovery, published in Science Advances on July 6, 2022, reveals a new vulnerability in the virus that could be targeted with drugs. "Structure informs function, and the insights we gained from visualizing the molecular architecture of Pol give us a new understanding of the mechanism by which HIV replicates," says co-senior author Dmitry Lyumkis, assistant professor in the Laboratory of Genetics and Hearst Foundation Developmental Chair at Salk. Scientists previously knew that HIV Pol, a polyprotein, breaks into three enzymes -- a protease, reverse transcriptase and integrase -- that work together to assemble the mature form of the virus. The protease plays a critical role in initiating this process by chopping up the molecule to separate the other components. However, it was previously unknown how the protease itself breaks free, first from the larger polyprotein HIV Gag-Pol and then from HIV Pol, to accomplish this task. The new paper suggests that the protease initiates the process by self-cleaving or cutting itself free from the rest of the molecule, aided by reverse transcriptase and, possibly, integrase. "It was known (but not understood) that there is a coupling between these enzymes before HIV Pol breaks apart. Visualizing the HIV Pol structure explains the basis for this complex mechanism," says co-senior author Eddy Arnold, board of governors professor and distinguished professor in the Center for Advanced Biotechnology and Medicine at Rutgers University. "The first challenge was producing a stable version of HIV Pol so the structure could be analyzed, which had never previously been reported," says co-first author Jerry Joe Harrison, senior lecturer at the University of Ghana. "This was a key missing piece of the HIV structural puzzle," adds Arnold. The team used cryogenic electron microscopy, an imaging technique to which Lyumkis has made important contributions, to reveal the three-dimensional structure of the HIV pol protein molecule. This led to the discovery that Pol is a dimer, meaning it's formed by two proteins bound together. The finding was a surprise because other similar viral proteins are single-protein assemblies. The group showed that in this two-sided structure, the protease component of Pol is "loosely tethered" to the reverse transcriptase component in a binding configuration that keeps the protease slightly flexible. "It's holding the protease at arm's length, loosely, and we believe that gives the protease a little bit of movement, which in turn allows it to initiate the cutting of polyproteins that is a prerequisite for viral maturation," says co-first author Dario Passos, a former researcher in Lyumkis' lab at Salk. "Current HIV treatments include multiple classes of inhibitors for all three enzymes, and the discovery also reveals a new vulnerability that could be targeted with drugs." The authors say the discovery opens the door for important follow-up research, including studies of the structure of the larger and more complex polyprotein Gag-Pol, also involved in viral assembly, as well as taking a closer look at the role of integrase in assembling the mature form of the HIV virus during replication. Other authors included Jessica F. Bruhn of Salk; Joseph Bauman, Lynda Tuberty and Francesc Xavier Ruiz of Rutgers; and Jeffrey DeStefano of the University of Maryland. The work was funded by the National Institutes of Health, International Institute of Education, Fulbright program, Margaret T. Morris Foundation and Hearst Foundations.