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Ever since James Watson and Francis Crick derived the double-helix model for the structure of DNA in 1953, the field of genomics has exponentially burgeoned into a vast array of molecular technologies. Of the current assortment of available genomic tools, next-generation sequencing (NGS) has proven to be of great value, particularly in the field of infectious disease. Here, the knowledge of DNA and RNA sequences has become indispensable for a variety of applications, including microbial identification and detection, evaluating the evolution and regulation of virulence, identifying drug resistance markers, detecting antigenic targets for vaccine development, and delineating community outbreaks.

NGS technologies are typically described as non-Sanger-based high-throughput DNA sequencing platforms that enable the analysis of millions of DNA fragments in parallel ¹. This ability to multiplex provides unprecedented scalability and has contributed to a gradual reduction in reagent costs, allowing whole-genome sequencing (WGS) to become accessible and practical to researchers around the world. Over the last decade, a number of platforms and methods have been developed that enable de novo sequencing, re-sequencing, transcriptome profiling, and cDNA sequencing.

In the field of infectious disease, NGS affords a means for reviewing the complete genetic make-up of microbial pathogens through de novo sequencing or re-sequencing, regardless of the fastidious or non-fastidious nature of the strain. This ability to review an entire genome, or individual genes or operons, provides a unique opportunity for clinical diagnostics, the identification of potential antigenic targets for vaccine development, and epidemiological surveillance. Currently, the diagnosis of microbial infections typically begins with patient observation and the collection of specimens for microbiological processing for various diagnostic tests. Depending on the causative agent, these diagnostics tests may include serology and analyzing specimens for the presence of immune cells via microscopy. For some bacterial infections, culture-based growth techniques, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and polymerase chain reaction (PCR) are also used for microbial identification and analysis. If employed, NGS could potentially be used to identify a pathogen without prior knowledge of the target, as well as discern the presence of any virulence determinants or genes conferring drug resistance ²⁻⁴. In turn, this would provide an additional clinical tool that may help patients receive a more precise diagnosis and efficient treatment regimen.

In addition to clinical diagnostics, NGS offers a potential tool for vaccine development and evaluation. For example, NGS can allow for the surveillance of pathogen evolution. For rapidly mutating pathogens such as the influenza virus, this could provide an opportunity to help identify antigenic drift within the microbial population and use that knowledge to create a better, more specific vaccine. NGS could also be used for reverse vaccinology, where pathogen sequences are used to identify putative surface antigens that could potentially be targeted for the development of a novel vaccine preparation ⁴. In accordance with this latter application, the expression of the putative surface antigens can also be examined through the evaluation of RNA sequences during different stages throughout the pathogen life cycle. As some strains require more than one species for survival and replication, analyzing RNA expression can help ensure that the vaccine target is actively expressed in the human host to ensure an efficient immunological response. Lastly, NGS could be applied in vaccine safety analyses by detecting the presence of viral contaminants in cell culture used in vaccine development or identifying virulent mutations in live-attenuated vaccines prepared with highly pathogenic, genetically unstable strains prior to the use of the vaccine 5,6. Overall, NGS could help contribute to the development of safer vaccines that provide a more effective immune response.

Lastly, NGS is gradually being employed in the epidemiological analysis of cultures for outbreak detection and infection control. Using genomics, outbreak strains have been identified at the species level and below with extraordinarily high resolution. Through the analysis of these strains, population genetic studies can contribute to a better understanding of important genetic markers among strains while also tracking transmission events during outbreaks. In turn, this allows for the development of a tailored control program to help limit the further spread of disease ⁷. A recent example of the use of NGS in epidemiological surveillance was during the analysis of a 2011 hospital outbreak of methicillin-resistant Staphylococcus aureus (MRSA) ⁸. Here, WGS was used to identify hospitalized infant patients infected with MRSA and determine the source of transmission. Through this study, 26 related cases of MRSA were identified and it was demonstrated that transmission occurred within the hospital between mother and patient, among mothers on a postnatal ward, and in the community. Moreover, WGS confirmed that MRSA carriage by a staff member allowed the outbreak to persist during periods of no known infection. Overall, this study demonstrated that NGS technology enabled a more precise identification of patients involved in an outbreak, allowing for the implementation of an effective infection control program that helped halt the spread of disease.

Despite the numerous advantages of NGS in the analysis of infectious diseases, there are a few challenges that may need to be overcome. For example, for NGS data to be reliable, particularly with regard to re-sequencing and microbial identification, it is important that validated sequence data is readily accessible. Well-renowned sequence databases (e.g. GenBank) provide an annotated collection of publically available genome sequences from authenticated type strains, such as those obtained from prominent biological resource centers like ATCC. As type strains are the nomenclatural origin of a species or subspecies, they are typically fully authenticated and exhibit all of the relevant phenotypic and genotypic properties described in original taxonomic circumscriptions, making them ideal reference standards for NGS. Extensive bioinformatics to analyze sequences from assembly to annotation, which necessitates expertise and time, could pose another challenge for NGS clinical use. This can be potentially circumvented through the development of automated tools for sequence analysis combined with the assemblage of exhaustive databases containing all known genome sequences ³. Lastly, there is the possibility that host DNA will be analyzed alongside microbial nucleic acids, which may make it difficult to discern the target genomics. To overcome this, the microbial to host nucleic acid ratio must be increased through procedures such as hydrolysis or chemical treatment ⁴.

In conclusion, clinical microbiology laboratories face a number of challenges regarding the diagnosis and effective treatment of infectious diseases. NGS could provide an additional insight to aid in clinical diagnostics while offering an effective mechanism for the identification of potential vaccine targets and a way to track outbreaks. Only through continual efforts in the advancement of this technology can NGS become fully ingrained in the field of infectious disease as a routine diagnostic tool.

1. Nature. Next-generation sequencing - Definition. http://www.nature.com/subjects/next-generation-sequencing, 2015.

2. Wain J, Mavrogiorgou E. Next-generation sequencing in clinical microbiology. Expert Rev Mol Diagn 13(3): 225-227, 2013.

3. Fournier PE, et al. Modern clinical microbiology: new challenges and solutions. Nat Rev Microbiol 11: 574-585, 2013.

4. Lecuit M, Eloit M. The diagnosis of infectious disease by whole genome next generation sequence: a new era is opening. Front Cell Infect Microbiol 4: 25, 2014.

5. Luciani F, et al. Next generation deep sequencing and vaccine design: today and tomorrow. Trends in Biotechnology 30(9): 443-452, 2012.

6. Neverov A, Chumakov K. Massively parallel sequencing for monitoring genetic consistency and quality control of live viral vaccines. Proc Natl Acad Sci 107(46): 20063-20068, 2010.

7. Tang P, Gardy JL. Stopping outbreaks with real-time genomic epidemiology. Genome Med 6(11): 104, 2014.

8. Harris SR, et al. Whole-genome sequencing for analysis of an outbreak of methicillin-resistant Staphylococcus aureus: a descriptive study. Lancet Infect Dis 13(2): 130-136, 2013.

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Using Next-Generation Sequencing for Infectious Disease Research - Understanding Microbial Pathogens from Within

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Ever since James Watson and Francis Crick derived the double-helix model for the structure of DNA in 1953, the field of genomics has exponentially burgeoned into a vast array of molecular technologies. Of the current assortment of available genomic tools, next-generation sequencing (NGS) has proven to be of great value, particularly in the field of infectious disease.

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A new tool developed at the Howard Hughes Medical Institute's Janelia Research Campus lets scientists shine a light on an animal's brain to permanently mark neurons that are active at a particular time. The tool -- a fluorescent protein called CaMPARI that was developed at Janelia -- converts from green to red when calcium floods a nerve cell after the cell fires. The permanent mark frees scientists from the need to focus a microscope on the right cells at the right time to observe neuronal activity.

Calcium-sensitive fluorescent molecules called GCaMP emit a fluorescent signal that indicates neural activity, and are useful for following the dynamics of neural networks. But their signal is temporary, and if researchers miss it because the microscope is not focused on the right spot in the brain, the information is lost. With CaMPARI, researchers can visualize neural activity beyond a microscope's limited field of view, capturing a snapshot of neural activity across wide swaths of brain tissue. The new tool also enables scientists to visualize neural activity during more complicated behaviors than previous calcium indicators, because in many cases it can be used while animals move freely, rather than being confined to a dish or embedded in agar.

"The most enabling thing about this technology may be that you don't have to have your organism under a microscope during your experiment," says Loren Looger, a group leader and protein chemist at Janelia who engineers tools to study the brain. "So we can now visualize neural activity in fly larvae crawling on a plate or fish swimming in a dish."

Looger, Eric Schreiter, and their colleagues report on CaMPARI and its ability to label active neural circuits in fruit flies, zebrafish, and mice in the February 13, 2015, issue of the journal Science.

Schreiter, a senior scientist in Looger's lab, led the development of CaMPARI, working as part of Janelia's Genetically-Encoded Neuronal Indicator and Effector (GENIE) project team. GENIE is an interdisciplinary team dedicated to engineering fluorescent sensors that facilitate the imaging of neuronal activity in living organisms. Project teams are like small start-up companies within Janelia and were created to tackle biological problems that require collaboration across multiple labs.

To make CaMPARI, the team started with a fluorescent protein called Eos. Eos emits a green fluorescence until it is exposed to violet light, which permanently alters the protein so that it fluoresces in red. "That was the perfect starting place," says Schreiter. "That conversion from green to red gives us a permanent signal. So we just needed a way to couple that conversion to the activity that's going on in the cell." To do that, the scientists incorporated a calcium-sensitive protein known as calmodulin, which makes the color change dependent on the burst of calcium that accompanies neural activity. It's the same domain that scientists added to fluorescent proteins to make calcium-responsive GCaMP sensors.

To find a useful protein that switches the color of its fluorescence only in the presence of both calcium and an activating violet light, the researchers made and screened tens of thousands of subtly different proteins. "When we finally got one that photoconverted more with calcium than without it, we knew we had a tool. We just needed to make it better to get it to the point where another neuroscientist could sit down and use it," says first author Ben Fosque, a graduate student in the biochemistry and molecular biophysics program at the University of Chicago.

The team spent more than a year tweaking their protein -- making it brighter and more responsive to calcium and ensuring that it would work in cells and then in living mice, fruit flies, and zebrafish. In the end, they had a tool that they named CaMPARI, which stands for calcium-modulated photoactivatable ratiometric integrator.

The need to use violet light in converting the protein's fluorescence gives experimenters control over the time period during which neural activity is tracked. "Ideally, we can flip the light switch on while an animal is doing the behavior that we care about, then flip the switch off as soon as the animal stops doing the behavior," Schreiter explains. "Then we're capturing a snapshot of only the activity that occurs while the animal is doing that behavior."

The scientists conducted a series of experiments to demonstrate CaMPARI's effectiveness. In one set of experiments, they captured a snapshot of neuronal activity over the entire brain volume of a zebrafish during a ten-second period as it swam in a dish. Following the experiment, CaMPARI was red in motor neurons known to be involved in swimming, as well as other expected sets of neurons--consistent with observations made by other scientists during electrophysiology experiments. The activation patterns changed significantly when the researchers altered the temperature or turbulence of the water.

In fruit flies, the team used CaMPARI to identify neurons that were activated in response to specific odors. Here too, the observations were as expected based on previous experiments: CaMPARI indicated that different odors activated distinct sets of neurons in the flies' antennal lobes. In a subsequent set of experiments, the researchers experimentally activated the neurons that directly responded to the odors, then looked for neurons elsewhere in the brain that subsequently turned red. Those experiments revealed neurons that Schreiter says may be secondary, tertiary, or even quaternary components to the olfactory circuits. Tracing a circuit from one neuron to the next is difficult under a microscope, the scientists say, because cell projections and their connections to other cells generally extend beyond the instrument's field of view.

With ongoing development, the scientists expect future versions of CaMPARI will be more sensitive and reliable than the current tool. But Looger says it's important to get CaMPARI into the hands of neuroscientists right away. "The idea is probably more powerful than the tool, as it stands right now," he says. "We will definitely benefit from a couple hundred -- hopefully a thousand -- labs taking CaMPARI and seeing what they can do with it."

To that end, the team has made the genetic plasmid encoding CaMPARI available through the plasmid repository Addgene; transgenic flies expressing CaMPARI are available through the Bloomington Drosophila Stock Center; and Janelia group leader Misha Ahrens is distributing CaMPARI-expressing zebrafish to researchers. Tools for introducing CaMPARI into mouse cells should be available soon, the scientists say.

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brain-computer interfaces; brain injury; neuroscience; intelligence; biotechnology; molecular biology; cell biology; genetics

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New fluorescent protein permanently marks neurons that fire

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A new tool lets scientists shine a light on an animal's brain to permanently mark neurons that are active at a particular time. The tool -- a fluorescent protein called CaMPARI -- converts from green to red when calcium floods a nerve cell after the cell fires.

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Credit: Janice Haney Carr/CDC
Not unlike an urban restaurant, the success of a bacterial cell depends on three things: localization, localization and localization. But the complete set of controls by which bacteria control the movement of proteins and other essential biological materials globally within the confines of their membrane walls has been something of a mystery. Now, researchers at the University of Washington have parsed out the localization mechanisms that E. coli use to sort through and organize their subcellular components.

"Despite their small size and relative simplicity, bacterial cells appear to possess a robust and complex level of subcellular organization, both spatially and temporally, that was once thought to only exist in more complex organisms," said Nathan Kuwada, a postdoctoral fellow in the lab of Paul Wiggins at the University of Washington.

"We wanted to know how many mechanisms bacteria possess to localize subcellular components, and to answer this question, we set out to image the localization pattern of nearly every protein in a bacterial cell for the entire cell cycle."

Kuwada will describe the group's findings this week at the Biophysical Society's 59th annual meeting in Baltimore, Md.

E. coli localize nearly one-fifth of their proteins to specific subcellular sites, but until now, the cell-cycle localization behavior of only a small subset of proteins had been characterized in detail.

Kuwada and his colleagues sought to remedy this by imaging an existing library of green-fluorescent protein fusions in E. coli by use of a high-throughput live-cell imaging scheme. This allowed them to image close to a thousand individual protein fusions in growing cells for 6-8 hours, providing them with hundreds of complete cell cycles for each protein.

Using custom image processing software, the researchers processed and organized the thousands of images from each experiment, allowing them to quantitatively compare the localization patterns on a genomic scale. The researchers also developed a public online database with all of their raw and processed data in a browsable and searchable form at: http://mtshasta.phys.washington.edu/localizome

Rather than a small number of patterns combining in various permutations determined by function, the researchers found that bacteria possess a large number of distinct patterns with subtle spatial and temporal differences.

For example, Kuwada and his colleagues also observed that the DNA-binding proteins were asymmetrically distributed towards the daughter cell during cell divisions, despite the morphological symmetry between parent and daughter cells.

"Although the asymmetry is somewhat weak, it is still statistically significant and we think it must have an exciting biological significance," Kuwada said. "This finding, which is only observable using our complete-cell-cycle approach, potentially has many biological consequences that we are currently trying to better understand."

Future work for Kuwada and his colleagues includes further exploring the specific mechanisms that drive subcellular organization, through targeting the behavior of specific groups of proteins such as transcription factors with increased precision.

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cell biology; molecular biology; bacteria; biology; biotechnology; genetics; biotechnology and bioengineering; microbiology

# data[].attributes.attachment_link.description
Not unlike an urban restaurant, the success of a bacterial cell depends on three things: localization, localization and localization. But the complete set of controls by which bacteria control the movement of proteins and other essential biological materials globally within the confines of their membrane walls has been something of a mystery.

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Stem cells that were claimed to be created simply by exposing ordinary cells to stress were probably derived from embryonic stem cells, according to the latest investigation into an ongoing scientific scandal. How that contamination occurred, however, remains an open question. Read more

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Credit: Steve Zylius / UC Irvine
UC Irvine and Australian chemists have figured out how to unboil egg whites -- an innovation that could dramatically reduce costs for cancer treatments, food production and other segments of the $160 billion global biotechnology industry, according to findings published today in the journal ChemBioChem.

"Yes, we have invented a way to unboil a hen egg," said Gregory Weiss, UCI professor of chemistry and molecular biology & biochemistry. "In our paper, we describe a device for pulling apart tangled proteins and allowing them to refold. We start with egg whites boiled for 20 minutes at 90 degrees Celsius and return a key protein in the egg to working order."

Like many researchers, he has struggled to efficiently produce or recycle valuable molecular proteins that have a wide range of applications but which frequently "misfold" into structurally incorrect shapes when they are formed, rendering them useless.

"It's not so much that we're interested in processing the eggs; that's just demonstrating how powerful this process is," Weiss said. "The real problem is there are lots of cases of gummy proteins that you spend way too much time scraping off your test tubes, and you want some means of recovering that material."

But older methods are expensive and time-consuming: The equivalent of dialysis at the molecular level must be done for about four days. "The new process takes minutes," Weiss noted. "It speeds things up by a factor of thousands."

To re-create a clear protein known as lysozyme once an egg has been boiled, he and his colleagues add a urea substance that chews away at the whites, liquefying the solid material. That's half the process; at the molecular level, protein bits are still balled up into unusable masses. The scientists then employ a vortex fluid device, a high-powered machine designed by Professor Colin Raston's laboratory at South Australia's Flinders University. Shear stress within thin, microfluidic films is applied to those tiny pieces, forcing them back into untangled, proper form.

"This method ... could transform industrial and research production of proteins," the researchers write in ChemBioChem.

For example, pharmaceutical companies currently create cancer antibodies in expensive hamster ovary cells that do not often misfold proteins. The ability to quickly and cheaply re-form common proteins from yeast or E. coli bacteria could potentially streamline protein manufacturing and make cancer treatments more affordable. Industrial cheese makers, farmers and others who use recombinant proteins could also achieve more bang for their buck.

UCI has filed for a patent on the work, and its Office of Technology Alliances is working with interested commercial partners.

Journal Reference:

Tom Z. Yuan, Callum F. G. Ormonde, Stephan T. Kudlacek, Sameeran Kunche, Joshua N. Smith, William A. Brown, Kaitlin M. Pugliese, Tivoli J. Olsen, Mariam Iftikhar, Colin L. Raston, Gregory A. Weiss. Shear-Stress-Mediated Refolding of Proteins from Aggregates and Inclusion Bodies. ChemBioChem, 2015; DOI: 10.1002/cbic.201402427

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human biology; genes; medical imaging; molecular biology; cell biology; biotechnology and bioengineering; biochemistry; organic chemistry; nature of water

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Chemists find a way to unboil egg whites: Ability to quickly restore molecular proteins could slash biotechnology costs

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from research organizations Credit: Steve Zylius / UC Irvine UC Irvine and Australian chemists have figured out how to unboil egg whites -- an innovation that could dramatically reduce costs for cancer treatments, food production and other segments of the $160 billion global biotechnology industry, according to findings published today in the journal ChemBioChem.

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Improving antibiotics to treat staph infections

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Improving antibiotics to treat staph infections

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In research published in Proceedings of the National Academy of Sciences, assistant professor of biochemistry and molecular biology at Saint Louis University Mee-Ngan F. Yap, Ph.D., discovered new information about how antibiotics like azithromycin stop staph infections, and why staph sometimes becomes resistant to drugs.

Her evidence suggests a universal, evolutionary mechanism by which the bacteria eludes this kind of drug, offering scientists a way to improve the effectiveness of antibiotics to which bacteria have become resistant.

Staphylococcus aureus (familiar to many as the common and sometimes difficult to treat staph infection) is a strain of bacteria that frequently has become resistant to antibiotics, a development that has been challenging for doctors and dangerous for patients with severe infections.

Yap and her research team studied staph that had been treated with the antibiotic azithromycin and learned two things: One, it turns out that the antibiotic isn't as effective as was previously thought. And two, the process that the bacteria use to evade the antibiotic appears to be an evolutionary mechanism that the bacteria developed in order to delay genetic replication when beneficial.

The team studied the way antibiotics work within the ribosome, the site where bacteria translates the genetic codes into protein. When the bacteria encounter a potential problem in copying its genetic material, as posed by an antibiotic, it has a mechanism to thwart antibiotic inhibition by means of "ribosome stalling" that is mediated by special upstream peptide elements.

As the bacteria's ribosome copies the strings of genetic code, "ribosome stalling" at upstream elements often promotes the rearrangement of messenger RNA and activates downstream translation of the resistance gene.

Many resistant pathogens exploit this mechanism to up-regulate antibiotic resistance genes, and so survive even in the presence of antibiotics. In effect, the delay allows the bacteria to prepare a defense against the antibiotic further down the line of genetic code.

Yap found that the azithromycin-bound ribosomes do not simply stall at random residues, but only at specific sites. Intriguingly these residues seem to be the preferred stalling site in the "ribosome stalling" peptide elements that stop genetic activity.

"Here we describe, to our knowledge, the first genome-wide snapshot of ribosome distribution along messenger RNAs in Staphylococcus aureus," Yap said. "By globally mapping the position of stalled ribosomes in azithromycin-treated staph, we identified the proteins affected by this antibiotic.

"Our results reveal a striking similarity of stalling motifs that strongly suggests a universal stalling mechanism," Yap said. "We have identified what appears to be an evolutionary mechanism developed by bacteria to counteract the type of antibiotics that includes azithromycin, called macrolides."

Yap hopes this new understanding of how antibiotic resistance occurs will offer opportunities to improve existing drugs' effectiveness and give doctors more tools to help patients with severe infections.

Journal Reference:

A. R. Davis, D. W. Gohara, M.-N. F. Yap. Sequence selectivity of macrolide-induced translational attenuation. Proceedings of the National Academy of Sciences, 2014; 111 (43): 15379 DOI: 10.1073/pnas.1410356111

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infectious diseases; pharmaceuticals; pharmacology; wounds and healing; genes; today's healthcare; tuberculosis; gene therapy

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Improving antibiotics to treat staph infections

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New information about how antibiotics like azithromycin stop staph infections has been uncovered, including why staph sometimes becomes resistant to drugs. Staphylococcus aureus (familiar to many as the common and sometimes difficult to treat staph infection) is a strain of bacteria that frequently has become resistant to antibiotics, a development that has been challenging for doctors and dangerous for patients with severe infections.

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Bacteria communicate by means of chemical signals and can develop common characteristics through this "agreement" and also develop their potential pathogenic effects in this way. Scientists working with Dr. Helge B. Bode, an Merck-endowed professor for molecular biotechnology at the Goethe University in Frankfurt, and Dr. Ralf Heermann from the department of microbiology at the Ludwig Maximilian University in Munich, have now described a hitherto unknown communication pathway that appears to be widely distributed.

They report on this in the journal Proceedings of the National Academy of Science.

The investigation of bacterial communication is also of medical interest. This is because the bacterial communication pathways are a possible therapeutic target for new medicines. If the relevant communication options are prevented, the bacteria cannot develop their pathogenic properties. "When pathogens are no longer destroyed by antibiotics as we have seen to date, but rather be impaired beforehand the formation of the pathogenic properties, the danger of resistance development would be substantially reduced," says Bode.

Different types of bacteria also have different methods of communication. The team lead by Heerman and Bode had already discovered a new bacterial communication pathway in 2013. Now they have succeeded in decoding a further new and widely distributed chemical type of bacterial communication.

To date, the best known communication between bacteria occurs via the N-acyl homoserine lactone (AHL): The enzyme Luxl produces signals that are recognised by the LuxR receptor, at which point the bacteria develop certain properties and modulate their behaviour towards one another. Since a certain number of bacteria must be available for this to occur, this process is known as "quorum sensing."

However, Heermann's and Bode's working groups investigate bacteria that possess a LuxR receptor, but not the enzyme Luxl. In the current study, the microbiologists have investigated the bacteria Photorhabdus asymbiotica, which is a deadly pathogen in insects, which also infects humans and can cause skin infections. These bacteria communicate via the signal molecule dialkylresorcinol, which recognised the associated LuxR receptor. "The influence on the pathogenic properties of the bacteria is at its strongest in this 'quorum sensing' system. P. asymbiotica requires dialkylresorcinol and in this way coordinates the communication with the conspecifics for the successful infection of the larvae," says Helge Bode, whose group in 2013 also described the biosynthesis of this new signal molecule.

The researchers have not only investigated P. asymbiotica, but also a series of other bacterial genomes. The newly discovered signal pathway appears to be widely distributed. "We were able to identify several other bacteria that are pathogenic to humans that also do not express Luxl and also possess this ability for forming these signals," says Heerman.

Journal Reference:

Sophie Brameyer, Darko Kresovic, Helge B. Bode, Ralf Heermann. Dialkylresorcinols as bacterial signaling molecules. Proceedings of the National Academy of Sciences, 2015; 112 (2): 572 DOI: 10.1073/pnas.1417685112

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bacteria; microbes and more; microbiology; new species; extreme survival; biotechnology and bioengineering; fungus; molecular biology

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New bacterial 'language' discovered: Previously unknown communication pathway

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Bacteria communicate by means of chemical signals and can develop common characteristics through this "agreement" and also develop their potential pathogenic effects in this way. Scientists have now described a hitherto unknown communication pathway that appears to be widely distributed.

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Artificial Mini-Stomachs Made in the Lab

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Artificial Mini-Stomachs Made in the Lab

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After building the product for Huffington Post, and owning the product and engineering groups at AOL after we were acquired, it was clear to me there was a huge gap between what the current CMS offering gave the world and what the world needed. Five years later we are at scale, moving the needle and doing to WordPress what Airbnb did to Craigslist.

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You might have the feeling we could go on a bit longer. We could! This is a passion for us. Come talk to us and let's get growing together.

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Kary Mullis: A next-gen cure for killer infections

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Drug-resistant bacteria kills, even in top hospitals. But now tough infections like staph and anthrax may be in for a surprise. Nobel-winning chemist Kary Mullis, who watched a friend die when powerful antibiotics failed, unveils a radical new cure that shows extraordinary promise.

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A new breakthrough could end our antibiotic crisis

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A new breakthrough could end our antibiotic crisis

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Quartz-Angelika Grundling

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The rise of bacteria that are resistant to antibiotics is a growing worry and threatens to put healthcare back to the early 20th century. Such resistance to drugs was inevitable, because bacteria evolve and learn to defend themselves. But we are worried now because new classes of antibiotics aren't being found.

Now we may have to worry a little less. Researchers have discovered a new drug, called teixobactin, which marks the launch of a new class of antibiotics. Better still, they show that even highly sensitive bacteria may not easily develop resistance to this new antibiotic.

Beyond the discovery of the drug, their study published in Nature is remarkable for another reason. The technology developed by these researchers could herald the discovery of many new classes of antibiotics.

How iChip works

In a single scoop of soil, bacteria and fungi number in the millions. They also come in thousands of varieties, and survive by fighting each other. We know this because for the past century, several newly discovered antibiotics have been found by isolating them from the bacteria and fungi that produce them to defend their own lives.

The trouble, however, is that only about 1% of the microbes in the soil (or sea water) can be reliably grown under lab conditions. This means that so far we have not been able to study the remaining 99%, which are bound to produce antibiotics unknown to us.

This is the problem Kim Lewis and Slava Epstein at Northeastern University in Boston and colleagues have been busy trying to solve. After more than a decade of work, they have a solution in the iChip technology.

To make it work, a sample of soil is diluted and then poured on the iChip, which consists of hundreds of small holes. Because of the dilution, it is hoped that only one microbe is caught in each hole.

Losee L. Ling et al / Nature

The iChip is then covered with membranes on both sides and put back into the soil sample. The membranes contains pores that are only large enough for chemical nutrients to flow in but small enough to block the movement of any bacteria. This means the single bacteria in each of the holes in the iChip can consume all the nutrients it would naturally find in the environment and multiply, but not be contaminated with other bacteria in the soil.

Remarkably, it has been shown that this method can help nearly one in two bacteria to start growing in the iChip cells. Better still, three-quarters of the iChip bacteria can then be transferred to and grown in lab solutions. Quite the improvement from the 1% that could be previously grown in labs.

Why this transition through the iChip allows previously incapable bacteria to grow in lab solutions is not clear, but it may have to do with mutations gained by the bacteria during the process. And this step is crucial because it might help to overcome a huge barrier that was stopping the development of new antibiotics-growing bacteria under lab conditions to study and isolate the antibiotics they produce.

From soil to pills

Because Lewis was able to grow some of the soil bacteria to a large scale, he could isolate the antibiotics they produced to test if any of them were new. One bacteria, called Eleftheria terrae, was found to produce the best antibiotic candidate, which became teixobactin.

An analysis of teixobactin reveals that it attacks an essential precursor required for the production of cell walls in bacteria. Although it is not the first antibiotic to attack cell walls, it is able to do so quite effectively, albeit in petri-dishes and in mice.

But teixobactin attacks only Gram-positive bacteria, which have a thick cell wall but lack an outer membrane and cause diseases such as diphtheria and tetanus. Gram-negative bacteria are further protected by an outer membrane and this makes them insensitive to the antibiotic. So infections with Gram-negative bacteria often even more problematic to treat when it comes to drug-resistance and will need to be attacked with a different antibitoic.

The chances of teixobactin becoming a drug suitable for humans is currently hard to estimate. But the odds of a drug candidates that works in mice making it through the clinical trials process is in general slim. And if Teixobactin does not make it, it could be chemically modified to make it work in humans. Crucially, though, Lewis's technology has the potential to lead to the discovery of other new classes of antibiotics.

The greatest developments in science are often not the discoveries but the developments that enable them. So while teixobactin is certainly a remarkable achievement, the new method to grow soil bacteria in labs is an equally important contribution that Lewis and his team have made.
This post originally appeared at The Conversation. Follow @US_conversation on Twitter. We welcome your comments at ideas@qz.com.

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A new breakthrough could end our antibiotic crisis

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The rise of bacteria that are resistant to antibiotics is a growing worry and threatens to put healthcare back to the early 20th century. Such resistance to drugs was inevitable, because bacteria evolve and learn to defend themselves. But we are worried now because new classes of antibiotics aren't being found.