Luallen Lab members pose in their lab at SDSU. Inset: Microscope image of Bordetella atropi (pink lines) infecting roundworm intestine (green). Credit: San Diego State University
Like something out of a horror movie, a new way that one type of bacteria invades tissue within a living organism has been identified by biologists from San Diego State University.
The study, published in Nature Communications, describes how a new species of bacteria, Bordetella atropi, invades its roundworm host. The name which comes from the Greek fate Atropos responsible for cutting the threads of life, is apt because the bacteria transforms into a long thread, growing up to 100 times the usual size of one bacterium in the span of 30 hours without dividing.
By altering the genes of B. atropi, the research team discovered that this invasive threading relies on the same genes and molecules that other bacteria use when they are in a nutrient-rich environment. However, these other bacteria only use this pathway to make subtly larger cells, whereas the B. atropi bacteria grows continuously.
Other bacteria often transform into threads, called filamentation, in response to dangerous environments or DNA damage. This lets them continue to grow in size, but delay cell division until they repair the damage inflicted by the stress.
Here, however, the researchers were the first to observe filamentation as a way of spreading from cell to cell in a living organism for a purpose other than the stress response. They believe that instead the new species is invading the host cells, detecting this rich environment and triggering filamentation in order to quickly infect more cells and access additional nutrients for their growth.
“We went from finding the worm in the ground, finding the bacteria, and carrying it all the way to the molecular mechanism of how the bacteria infects the worm,” explained Robert Luallen, biology professor and principal investigator of the study. “We’re seeing things that no one’s ever seen before.”
Though B. atropi does not infect humans, it is possible that human pathogens may also make use of its spreading mechanism. Separately, the nutrient-induced filamentation process might be used by other bacteria to form biofilms, which can coat the tubing of catheters and lead to complications for patients.
In a new publication in the journal Science, researchers propose that NFTs, or nonfungible tokens, could help patients assert better control over their personal health information.
NFTs, or nonfungible tokens, created using blockchain technology, have been a big sensation in the art world as they serve as a platform to buy and sell digital art backed by a digital contract. Now, an international multidisciplinary team of scholars in ethics, law and informatics led by bioethicists have written one of the first commentaries on how this new emerging technology could be repurposed for the healthcare industry. NFT digital contracts could provide an opportunity for patients to specify who can access their personal health information and to track how it is shared.
“Our personal health information is completely outside of our control in terms of what happens to it once it is digitised into an electronic health record and how it gets commercialised and exchanged from there,” said Dr Kristin Kostick-Quenet, first author of the paper. “NFTs could be used to democratise health data and help individuals regain control and participate more in decisions about who can see and use their health information.”
“In the era of big data, health information is its own currency; it has become commodified and profitable,” said Dr Amy McGuire, senior author of the paper and Leon Jaworski Professor of Biomedical Ethics and director of the Center for Medical Ethics and Health Policy at Baylor. “Using NFTs for health data is the perfect storm between a huge market place that’s evolving and the popularity of cryptocurrency, but there are also many ethical, legal and social implications to consider.”
Presently, NFTs are still vulnerable to data security flaws, privacy issues, and disputes over intellectual property rights, the researchers noted. The complexity of NFTs may also prevent the average person from properly making use of them. The researchers believe it is important to consider potential benefits and challenges as NFTs emerge as a potential avenue to transform the world of health data.
In a research paper published in Communications Biology, researchers from the University of Limerick have detailed the development and structure of the mesentery. In doing this, they uncovered a new order by which all contents of the abdomen are organised or arranged – or the “fundamental order of the abdomen”, where organs are in one of two compartments.
Professor Calvin Coffey, Foundation Chair of Surgery at UL’s School of Medicine in Ireland, whose major discovery led to the reclassification of the mesentery as a new organ in 2016, has published new research on the makeup and structure of the abdomen.
The importance of these findings on the mesentery and the impact these have on our understanding of the abdomen have been further explained in a review article just published in the Lancet Gastroenterology and Hepatology.
Prof Coffey explained that his team have been looking at the development and structure of the mesentery since 2016.
“We showed how the mesentery is a single and continuous organ in and on which all abdominal digestive organs develop and then remain connected to throughout life,” he explained.
“These findings revealed a simplicity in the abdomen that was not apparent in conventional descriptions of anatomy.”
The international team of researchers used cutting edge techniques to clarify how the mesentery develops and the shape it has in adults.
Their work revealed that the organisation of the abdomen has a remarkably simple design.
“The abdomen is not the dauntingly complex collection of separate organs it was previously thought to be,” said Prof Coffey.
“Instead, all digestive organs are neatly packaged and arranged by the mesentery into a single digestive engine. That simplicity lay hidden until clarification of the nature of the mesentery.”
“The most important finding here was the discovery of the fundamental order of the abdomen. At the foundation level, all contents of the abdomen are simply organised into one of two compartments,” explained Prof Coffey.
“The fundamental order of any structure is of considerable importance, in particular when it comes to diagnosing patients with illness and treating their disease. The fundamental order is the foundation from which all science launches and clinical practice is based.
“The organisational simplicity of the abdomen now immediately explains the behaviours of viral and bacterial infections, cancer, inflammatory bowel disease, obesity, diabetes and many others,” he added.
Improvements in surgery have been made to surgery by a better understanding of the mesentery and its functions, and the new research builds on those advances. There are also exciting areas for future investigation, according to Prof Coffey.
“Patients are already benefiting from what we now call mesenteric-based approaches to the diagnosis and treatment of most abdominal conditions. The Mesenteric Model of Abdominal Anatomy – or the description of the order of the abdomen – is being incorporated into numerous reference curricula at this moment,” he said.
“Regarding the future, it is being argued that we are seeing a paradigmatic shift from old to new order. Already, intriguing questions are emerging that we can call ‘legitimate or admissible’ in the strictest scientific sense. Science can approach numerous questions in a new light. Clinicians can design diagnostic and treatment approaches based on a new foundation,” Prof Coffey concluded.
In a significant step toward fully automated surgery on humans, a robot has performed laparoscopic surgery on the soft tissue of a pig without human guidance.
Designed by a team of Johns Hopkins University researchers, the Smart Tissue Autonomous Robot (STAR) is described in Science Robotics.
“Our findings show that we can automate one of the most intricate and delicate tasks in surgery: the reconnection of two ends of an intestine. The STAR performed the procedure in four animals and it produced significantly better results than humans performing the same procedure,” said senior author Axel Krieger, PhD, an assistant professor at John Hopkins University.
The robot excelled at intestinal anastomosis, which connects the two ends of an intestine. It is a procedure that requires a high level of repetitive motion and precision and is arguably the most challenging step in gastrointestinal surgery, requiring a surgeon to accurately and consistently suture. A slight hand tremor or misplaced stitch can result in a leak with potentially catastrophic complications for the patient.
The team developed a vision-guided system designed specifically to suture soft tissue. Their current iteration advances a 2016 model that repaired a pig’s intestines accurately, but required a large incision to access the intestine and more guidance from humans.
The team equipped the STAR with new features for enhanced autonomy and improved surgical precision, including specialised suturing tools and state-of-the art imaging systems that provide more accurate visualisations of the surgical field.
Soft-tissue surgery is especially hard for robots because of its unpredictability, forcing them to be able to adapt quickly to handle unexpected obstacles, Dr Krieger said. STAR features a novel control system that can adjust the surgical plan in real time, just as a human surgeon would.
As the medical field moves towards more laparoscopic approaches for surgeries, it will be important to have an automated robotic system designed for such procedures to assist, Dr Krieger said.
“Robotic anastomosis is one way to ensure that surgical tasks that require high precision and repeatability can be performed with more accuracy and precision in every patient independent of surgeon skill,” Dr Krieger said.
“We hypothesise that this will result in a democratised surgical approach to patient care with more predictable and consistent patient outcomes.”
By combining blood glucose measurement with insulin administration in a single device, the complicated process of blood sugar management could be made easier for people with diabetes.
Patients with diabetes often use two types of insulin to control their blood sugar levels: long-acting insulin, which helps control glucose levels over a 24-hour period, and short-acting insulin, which is injected at mealtimes. Patients first measure their blood glucose levels with a glucose meter with a finger prick. They must also estimate how many carbohydrates are in their meal and combine this information with their blood glucose levels to calculate and inject the proper insulin dose.
Existing technologies such as continuous blood glucose monitors and insulin pumps can help with some parts of this process. However, these devices are not widely available, so most patients must rely on finger pricks and syringes. To this end, MIT researchers have developed devices to simplify the process, which they describe in the Journal of Controlled Release.
“Every day, many patients need to do this complicated procedure at least three times,” explained MIT postdoc Hen-Wi Huang. “The main goal of this project is to try to facilitate all of these complex procedures and also to eliminate the requirement for multiple devices. We also used a smartphone camera and deep learning to create an app that identifies and quantifies food content, which can aid in carbohydrate counting.”
The researchers came up with two all-in-one devices, both of which incorporate the new smartphone app. Using a photo, the app estimates the volume of food and carbohydrate content.
The first device that consolidates many of the existing tools that patients use now, including a lancet for drawing blood and glucose test strips. The device conveys blood glucose information to the smartphone app via Bluetooth, and the app works out the correct insulin dose, delivered via a needle in the same device.
“What our device is doing is automating the procedures to prick the skin, collect the blood, calculate the glucose level, and do the computation and insulin injection,” Dr Huang says. “The patient no longer needs a separate lancing device, glucose meter, and insulin pen.”
Many of the components included in this device are already FDA-approved, but the device has not been tested in human patients yet. Tests in pigs showed that the system could accurately measure glucose levels and dispense insulin.
For their second device, the researchers wanted to come up with a system that would require just one needle prick. To achieve that, they designed a novel glucose sensor that could be incorporated into the same needle that is used for insulin injection.
The researchers designed a flexible electronic sensor that can be attached to the needle and measure glucose levels in the interstitial fluid, just below the surface of the skin. Once the needle penetrates the skin, it takes between five and 10 seconds to measure the glucose levels. This information is transmitted to the smartphone app, which calculates the insulin dose and delivers it through the inserted needle.
In tests in the pigs, the researchers showed that they could accurately measure glucose levels with this system, and that glucose levels dropped after insulin injection.
Because this device uses a novel type of glucose sensor, the researchers expect that it will require further development to get to a point where it could be tested in patients.
Experts from a data-driven initiative to aid the COVID response have outlined major obstacles to making successful use of new data released by technology companies in times of crisis. Harvard University’s Caroline Buckee and colleagues presented these views in the open-access journal PLOS Digital Health.
Technology companies collect vast amounts of data on their users, including their geographic locations. During the COVID pandemic, many companies made some of their user data available in order to aid public health efforts, such as monitoring the impact of social distancing policies or travel restrictions. However, Buckee and colleagues note, many efforts to harness these “data for good” failed to make a significant impact.
The authors are part of Crisis Ready, in which epidemiologists help policy makers understand and use insights from human mobility data released by technology companies. In this capacity, they have now identified challenges that hinder other efforts to use novel forms of data as part of disaster response.
Firstly, data-sharing agreements between researchers and technology companies were hastily arranged during the pandemic. They recommend pre-established agreements that will be ready for implementation in future crises.
Buckee and colleagues also observed that a lack of standardisation, interoperability, and clarity on uncertainties or biases in novel datasets resulted in the need for highly specialised professionals to process this data. To address this challenge, data access and characteristics can be negotiated prior to a disaster.
The authors also call for global investment in training more professionals that can analyse complex data to provide information in a disaster. In addition, they strongly emphasise the need for local response agencies to collaborate closely with regional scientists.
Without such efforts, no amount of data donated by technology companies will be useful in a crisis.
“It is still very difficult to translate the vast amounts of digital data that are owned by companies into useful public health tools, despite their incredible potential for transforming decision-making during health emergencies,” said Buckee. “We need to build a global cohort of data scientists and epidemiologists who can support local governments, and put in place the data pipelines and analysis tools before disasters hit, so that local responders have context-specific information when they need it most.”
Upon injection into the blood, nanomedicines (blue spheres) are immediately attacked by proteins of the immune system called complement proteins (orange). Complement proteins cause rapid destruction of the nanomedicine, and also induce an anaphylaxis-like reaction. By attaching complement-degrading proteins (yellow ninjas made of protein) to the surface of nanomedicines, Penn researchers have largely solved this problem, potentially allowing more diseases to be safely treated by nanomedicine. Credit: University of Pennsylvania
In nanomedicine, immune reactions against the nanoparticles that contain the medicine or vaccine, reducing its effectiveness. Researchers have now come up with a new method to prevent the body from treating nanomedicines like foreign invaders, by covering those nanoparticles with a coating to suppress the immune response.
As soon as they are injected into the bloodstream, unmodified nanoparticles are swarmed by complement proteins, triggering an inflammatory response and preventing the nanoparticles from reaching their treatment targets. Penn Medicine researchers, whose findings are published in Advanced Materials, have devised a coating for nanoparticles that suppresses complement activation.
Nanoparticles are tiny capsules, typically made from proteins or fat-related molecules, that contain certain types of treatment or vaccine. The best-known examples of nanoparticle-delivered medicines are mRNA COVID vaccines.
“It turned out to be one of those technologies that just works right away and better than anticipated,” said study co-senior author Jacob Brenner, MD, PhD.
RNA- or DNA-based therapies generally need delivery systems to get them through the bloodstream into target organs. Harmless viruses often have been used as carriers or “vectors” of these therapies, but nanoparticles are increasingly considered safer alternatives. Nanoparticles also can be tagged with antibodies or other molecules that make them hone in precisely on targeted tissues.
The complement attack problem has been a serious impediment to nanomedicine. Circulating complement proteins treat nanoparticles as if they were bacteria, immediately coating nanoparticle surfaces and summoning macrophages to engulf them. Researchers have attempted to reduce the problem by pre-coating nanoparticles with camouflaging molecules, such as forming a watery, protective shell around nanoparticles using polyethylene glycol (PEG).
But nanoparticles camouflaged with substances like PEG still draw at least some complement attack. In general, nanoparticle-based medicines that move through the bloodstream (mRNA COVID vaccines are injected into muscle, not the bloodstream) have had a very low efficiency in getting to their target organs, usually under 1%.
In the study, the researchers came up with a new approach to protect nanoparticles, based on natural complement-inhibitor proteins that circulate in the blood, attaching to human cells to help protect them from complement attack.
In vitro tests using standard PEG-protected nanoparticles with one of these complement inhibitors, called Factor I, provided dramatically better protection from complement attack. In mice, the same strategy prolonged the half-life of standard nanoparticles in the bloodstream, allowing a much larger fraction of them to reach their targets.
“Many bacteria also coat themselves with these factors to protect against complement attack, so we decided to borrow that strategy for nanoparticles,” said co-senior author Jacob Myerson, PhD, a senior research scientist in the Department of Systems Pharmacology and Translational Therapeutics at Penn.
In a set of experiments in mouse models of severe inflammatory illness, the researchers also showed that attaching Factor I to nanoparticles prevents the hyper-allergic reaction that otherwise could be fatal.
Further testing will be needed before nanomedicines incorporating Factor I can be used in people, but in principle, the researchers said, attaching the complement-suppressing protein could make nanoparticles safer and more efficient as therapeutic delivery vehicles so that they could be used even in severely ill patients.
The researchers now plan other protective strategies for medical devices, such as catheters, stents and dialysis tubing, which are similarly susceptible to complement attack. They also plan to investigate other protective proteins.
“We’re recognising now that there’s a whole world of proteins that we can put on the surface of nanoparticles to defend them from immune attack,” Dr Brenner said.
Astronaut Raja Chari sequences DNA from bacteria samples to understand the microbial environment on the International Space Station. Credit: NASA
The lack of gravity in outer space could be the key to the efficient production of large quantities of stem cells. Scientists at Cedars-Sinai have found that the microgravity environment in space stations can potentially aid life-saving advances on Earth by facilitating the rapid mass production of stem cells.
A new paper in Stem Cell Reports outlines key opportunities discussed at a space biomanufacturing symposium to expand the manufacture of stem cells in space.
With new rocket technology, the cost of access to space has plummeted, opening up new opportunities for research and industry, as well as spaceflight by private citizens. Biomanufacturing of therapeutic and research biomaterials can be more productive in microgravity conditions.
“We are finding that spaceflight and microgravity is a desirable place for biomanufacturing because it confers a number of very special properties to biological tissues and biological processes that can help mass produce cells or other products in a way that you wouldn’t be able to do on Earth,” said stem cell biologist Arun Sharma, PhD, head of a new Cedars-Sinai research laboratory.
“The last two decades have seen remarkable advances in regenerative medicine and exponential advancement in space technologies enabling new opportunities to access and commercialise space,” he said.
Attendees at the virtual space symposium in December identified more than 50 potential commercial opportunities for conducting biomanufacturing work in space, according to the Cedars-Sinai paper. The most promising fell into three categories: Disease modelling, biofabrication, and stem-cell-derived products.
Scientists use disease modelling, to study diseases and possible treatments by replicating full-function structures – whether using stem cells, organoids or other tissues.
Decades of spaceflight experience has shown that when the body is exposed to low-gravity conditions for extended periods of time, it experiences accelerated bone loss and ageing. By developing disease models based on this accelerated ageing process, research scientists can better understand the mechanisms of the ageing process and disease progression.
“Not only can this work help astronauts, but it can also lead to us manufacturing bone constructs or skeletal muscle constructs that could be applied to diseases like osteoporosis and other forms of accelerated bone ageing and muscle wasting that people experience on Earth,” explained Dr Sharma.
Biofabrication, another major topic of discussion at the symposium, produces materials like tissues and organs with 3D printing a core technology.
A major issue with biofabrication on Earth involves gravity-induced density, which makes it hard for cells to expand and grow. This requires the use of scaffolding structures, but it generally cannot support the small, complex shapes found in vascular and lymphatic pathways. With the lack of gravity in space, scientists are hopeful that they can use 3D printing to print unique shapes and products, like organoids or cardiac tissues, in a way that can’t be replicated on Earth. This technology is being tested on the International Space Station.
The third category has to do with the production of stem cells and understanding how some of their fundamental properties are influenced by microgravity. Some of these properties include potency, or the ability of a stem cell to renew itself, and differentiation, the ability for stem cells to turn into other cell types.
Understanding some of the effects of spaceflight on stem cells can potentially lead to better ways to manufacture large numbers of cells in the absence of gravity. In coming months, Cedars-Sinai scientists will send stem cells into space to test whether it is possible to produce large batches in a low gravity environment.
“While we are still in the exploratory phase of some of this research, this is no longer in the realm of science fiction,” Dr Sharma said. “Within the next five years we may see a scenario where we find cells or tissues that can be made in a way that is simply not possible here on Earth. And I think that’s extremely exciting.”
Using cannabis alongside other drugs may come with a significant risk of harmful drug-drug interactions, according to a pair of new studies in the journal Drug Metabolism and Disposition.
The researchers examined cannabinoids and their major metabolites found in the blood of cannabis users and found that they interfere with two families of enzymes that help metabolise a wide range of prescription drugs. Because of this, the drugs’ effectiveness might decrease or their negative effects might increase with too much building up in the body, causing unintended side effects such as toxicity or accidental overdose.
The authors note that despite the early stage of this research, it is important to be careful when using cannabis with other prescription drugs.
“Physicians need to be aware of the possibility of toxicity or lack of response when patients are using cannabinoids,” said Professor Philip Lazarus, senior author on the papers. “It’s one thing if you’re young and healthy and smoke cannabis once in a while, but for older people who are using medications, taking CBD or medicinal marijuana may negatively impact their treatment.”
One study focused on a family of enzymes known as cytochrome P450s (CYPs), whereas the other looked at UDP-glucuronosyltransferases (UGTs), another enzyme family. Together, these two enzyme families help metabolise and eliminate more than 70% of the most commonly used drugs from the body.
While some previous research focused on potential drug interactions caused by cannabinoids, this new research provides the first known comprehensive look at the interaction between three of the most abundant cannabinoids (tetrahydrocannabinol (THC), cannabidiol (CBD) and cannabinol (CBN)) and their metabolites and all of the major CYP enzymes. This is also the first known research that looked for interactions between these cannabinoids and UGT enzymes, specifically.
“Cannabinoids stay in your body only for about 30 minutes before they are rapidly broken down,” said first author Shamema Nasrin. “The metabolites that result from that process stay in your body for much longer – up to 14 days – and at higher concentrations than cannabinoids and have been overlooked in previous studies, which is why we thought we should focus on those as well.”
Using human kidney cells, they found that cannabinoids and the major THC metabolites strongly inhibited several CYP enzymes. One key discovery was that one of the most abundant THC metabolites, called THC-COO-Gluc seems to play a major role in inhibiting several key enzymes in the liver. Looking at the UGT enzyme family, the researchers found that all three cannabinoids, but especially CBD, inhibited two of the primary UGT enzymes present in the liver. CBD was also found to block three enzymes that account for about 95 percent of kidney UGT metabolism, which helps clear toxins and certain drugs from the body.
“If you have a kidney disease or you are taking one or more drugs that are metabolised primarily through the kidney and you’re also smoking marijuana, you could be inhibiting normal kidney function, and it may have long-term effects for you,” Prof Lazarus said.
Nasrin added that these interactions between CBD and UGT enzymes could be inhibiting kidney function in patients with acute kidney disease or kidney cancer, who may be using CBD to treat pain or to try to reduce the side effects from anti-cancer drugs.
“Taking CBD or marijuana might help your pain but could be making the other drug you’re taking more toxic, and that increase in toxicity may mean that you can’t continue taking that drug,” Nasrin said. “So, there could be serious ramifications for anti-cancer drugs, and that’s only one example of the many drugs that could potentially be affected by the cannabinoid-enzyme interactions we’re seeing.”
Capsule removal from Bacillus anthracis by treatment with Capsule Depolymerase (capsule shown in red). Credit: Photomicrograph by Wilson J. Ribot, USAMRIID
By modifying an enzyme produced by the bacterium that causes anthrax, US Army scientists were able to protect mice from infection with the deadly disease.
Their findings, published in Science Translational Medicine, suggest a potential therapeutic strategy for treating multidrug-resistant strains of anthrax, and could aid in the development of new treatments for other bacterial infections.
Bacillus anthracis, the bacterium that causes anthrax, is one of the most significant bioterrorism threats, as well as a public health challenge in many places around the world. Its disease-causing capability arised from three main components – lethal toxin, oedema toxin, and the capsule. Researchers in this study developed a method to degrade the capsule surrounding the bacterium, allowing it to be ingested and destroyed by white blood cells, reducing virulence.
There is increasing concern about strains of anthrax that appear to be resistant to treatment with known antibiotics, said Arthur M. Friedlander, MD, the paper’s senior author. He and his team explored alternative treatment approaches that do not rely on the use of antibiotic drugs.
One promising avenue is to make the bacterium more susceptible to the innate immune system. Enzymes known as capsular depolymerases, which are naturally produced by several classes of bacteria, have emerged as a potential new line of antivirulence agents.
“Identification of the capsule depolymerase enzyme within the anthrax bacillus led us to attempt to use that enzyme to remove the capsule,” said Friedlander. “When this proved successful, we utilised recombinant DNA technology and protein engineering methods to engineer and reconfigure the enzyme in new ways.”
Those “engineering changes” included enhancing stability and making production easier, and pegylation, to improve pharmacokinetics. The team then tested the pegylated enzyme, known as PEG-CapD-CPS334C, to be sure it had retained its enzymatic activity.
In the study, 10 out of 10 mice infected with anthrax spores from a nontoxigenic encapsulated strain were completely protected after treatment with PEG-CapD-CPS334C, compared to only 1 of 10 control mice surviving. Similarly, treatment of mice infected with a fully virulent encapsulated strain using PEG-CapD-CPS334C protected 8 of 10, while only 2 of 10 controls survived.
“This strategy renders B. anthracis susceptible to the innate immune responses and does not rely on antibiotics,” the authors concluded. “These findings suggest that enzyme-catalysed removal of the capsule may be a potential therapeutic strategy for the treatment of multidrug-resistant anthrax and other bacterial infections.”
It could also allow the treatment of soldiers exposed to anthrax through natural means or enemy attacks.
