Culture

The human immune system doesn't just protect our health, it reflects it. Each encounter with a potential disease-causing agent causes the body to produce specific immune agents -- proteins known as antibodies and T-cell receptors -- tailor-made to recognize and destroy the invader. Tasked with preventing re-infection, antibodies and T-cell receptors (TCR) from your previous encounters circulate throughout the body indefinitely, like a record of your personal medical history that you carry inside of you.

Clinical pathologist Ramy Arnaout, MD, DPhil, Associate Director of the Clinical Microbiology Laboratories at Beth Israel Deaconess Medical Center, wants to mine those personal medical records for information. In a recent perspective published in Frontiers in Immunology, Arnaout and colleagues in the Adaptive Immune Receptor Repertoire Community (AIRR-C) outline how the immunome -- all of the genes collectively expressed by an individual's immune cells -- holds the potential to provide researchers and physicians with unprecedented insight into an individual's health. Collecting that information from large numbers of patients could one day facilitate diagnostics via a near-universal blood test and pave the way to targeted therapies for a wide variety of conditions.

We asked Dr. Arnaout to tell us more about this new frontier of personalized medicine.

What exactly is the immunome and what can researchers and physicians learn from it?

The immunome is the complete set of immune cells -- antibodies and T cell receptors (TCR) -- that every person makes in response to infections, vaccinations, transplants and transfusions, autoimmune diseases, aging and cancers.

Right now, you have in your body something like a hundred billion to a trillion T and B cells, minding their own business, circulating through your blood, leaving to check out what's going on in all your organs, and then completing the loop and coming back around.

A number of us in the field have been thinking for some time that if we could just figure out which antibodies and T-cell receptors match to which disease or condition, then we would have a universal diagnostic. That is, we would be able to look at a person's antibodies and T-cell receptors, and just by seeing what's there, we'd be able to say, "Oh, these antibodies are against melanoma, that means you probably had it, but your immune system took care of it," or, "You probably had the flu."

One blood test, one jab -- everything else is computer science on the other end. But first we need to crack that code.

What could researchers and physicians do with this information?

If I looked at your immunome and your friend's immunome, you might assume that you'd have nothing in common. But, despite the underlying differences among us all, the antibodies and TCR we produce are similar enough even if they are not identical that scientists can look at them bioinformatically and recognize patterns.

We know now from data that despite extraordinary, unfathomable potential of diversity -- there are more different possible sequences than stars in the observable universe, certainly more than grams of mass in the sun -- you and I are not genetically that different. We live in the same world, we're sneezed on by the same people on the subway -- it is incredible that our actual diversity genetically is so unbelievably constrained that we have been able to and regularly do find patterns that we might have thought couldn't exist ten years ago.

So, by getting samples from people who have known conditions -- such as COVID-19, dengue, ebola and other infectious diseases -- and comparing them to control samples, scientists can computationally pull out patterns.

But the missing ingredient here is you. In this paper my colleagues and I just published in Frontiers in Immunology, we're trying to announce to the scientific community and beyond that we can find these patterns and put them to good use. But we need clinicians to be aware of this and connect with us.

For example, say an endocrinologist has a patient with a benign thyroid growth. In principle, we could take a sample of that patient's blood, find a sequence, and then use that sequence as an early diagnostic tool for future patients.

What technology is required to decode the immunome?

Step one was sequencing. Sequencing was the technology that made this kind of thinking possible. We now have the ability to sequence these antibody and TCR genes so that we can actually see what's in there.

Now that sequencing is more of a commodity, the frontier has moved to 'how can we find the patterns?' That's the mathematical and computational side of things, processing the sequencing data with artificial intelligence or machine learning algorithms.

But I don't want to overlook this third plank, even though it's not as splashy as sequencing and artificial intelligence: As I said before, the missing ingredient is you. We are past due for a nationwide, learning healthcare system.

Can we make sure that if a patient comes into a hospital in Massachusetts or Maine or Missouri, we can eventually get access to that blood sample that's about to be thrown out long after the patient has gone home, and sequence the millions of antibody and TCR genes it contains? And in addition to access to these discarded specimens across medical systems, we need them correlated to the information in electronic health records (EHR).

With the immunome, we have the chance again to use sequencing to learn about an individual's health, add that information to a database, correlate it to that person's health record, times millions of individuals -- we can untangle this code in relatively short order.

What is the good faith critique of this line of thought?

There is a point of view that if you want to diagnose an infection, for example, why look for the response? Just look for the infectious agent itself, right? Or if you want to see how person responds to cancer treatment, why look at the adaptive response of the immune as an indicator -- why not test cancer cells against drug? These are reasonable questions.

The answer is, the body takes a lot of these insults very seriously. Even if you have a rip-roaring, potentially life-threatening infection, the number of viable bacteria per milliliter of blood is vanishingly small -- around one viable bacterium per 5-10 milliliters of blood. Maybe there's a lot of bacteria somewhere in your body. But more typically, your body just takes infection with bacteria very seriously, so just a few bacteria are enough to set off a cascade of events that can kill you. Finding the actual bacteria, and distinguishing it from random bacterial DNA flotsam in the blood, is harder than it is to look at a person and say, "this person's white blood cell count is through the roof."

In other words, the immune response is not a proportional response, it's often a massively disproportionately response in many cases. It acts as a signal amplifier from a diagnostic perspective, and that's an advantage. If we can get enough samples to recognize a pattern, and if we can get enough samples, the track-record so far suggests we can determine what that signal is.

Why did you and your colleagues publish this Frontiers in Immunology paper now?

The Adaptive Immune Receptor Repertoire Community (AIRR-C) is a dedicated community that we wrote this paper with and on behalf of. We have the knowledge and expertise to lay the groundwork for the diagnostic potential of the immunome, but we can go so much faster with the help of others. That's why we are putting out a call to clinicians, researchers and others to join efforts with AIRR-C.

My hope is the next generation of doctors in medical school, when they hear about this they think, "I want to work on that."

This is the future of blood testing. It's a tremendously exciting time.

PHILADELPHIA - Lung cancer is the third most common cancer in the U.S. and the leading cause of cancer death, with about 80% of the total 154,000 deaths recorded each year caused by cigarette smoking. Black men are more likely to develop and die from lung cancer than persons of any other racial or ethnic group, pointing to severe racial disparities. For example, research has shown that Black patients are less likely to receive early diagnosis and life-saving treatments like surgery. Now researchers at Jefferson have found that a commonly used risk prediction model does not accurately identify high-risk Black patients who could gain life-saving benefit from early screening, and paves the way for improving screenings and guidelines. The research was published in JAMA Network Open on April 6.

"Black individuals develop lung cancer at younger ages and with less intense smoking histories compared to white individuals," explains Julia Barta, MD, Assistant Professor of Medicine in the Division of Pulmonary and Critical Care Medicine at Thomas Jefferson University, and researcher at the Jane and Leonard Korman Respiratory Institute. "Updated guidelines now recommend screening eligible patients beginning at age 50, but could still potentially exclude higher-risk Black patients. We are interested in finding methods that could help identify at-risk patients who are under-screened."

Screening for lung cancer is an annual CT scan to detect the presence of lung cancer in otherwise healthy people with a high risk of lung cancer. Current guidelines do not require a risk score for screening eligibility, but some researchers think that risk models could improve care. Risk prediction models are mathematical equations that take into account risk factors like smoking history and age to produce a risk score, which indicates the risk for developing lung cancer. Existing risk prediction models are derived from screening data that only include 5% or fewer African American individuals.

"What makes our study unique is that our screening cohort included more than 40% Black individuals," says senior author Dr. Barta, a member of Sidney Kimmel Cancer Center - Jefferson Health. "To our knowledge, our study is the first to examine lung cancer risk in a diverse screening program and aims to strengthen the argument for more inclusive guidelines for screening eligibility."

The most well-validated model used in screening research is the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial modified logistic regression model (PLCOm2012). "It uses 10-12 risk factors that include age, race, smoking history, as well as some socioeconomic factors like education to calculate a risk score," says Christine Shusted, MPH, first author of the study and research data analyst for Jefferson's Lung Cancer Screening Program through the Korman Respiratory Institute at Thomas Jefferson University. "The higher the score, the higher the risk of developing lung cancer. We wanted to see how well this model identifies patients with the highest risk of lung cancer in this diverse patient population."

The researchers conducted a cross-sectional, retrospective study in 1,276 Black and white patients (mean age, 64.25 years; 42.7% Black; 59.3% women) who enrolled in the Jefferson Lung Cancer Screening Program between January 2018 and September 2020. From this screening cohort, lung cancer was detected in 32 patients, 44% of whom were Black - these patients formed the cancer cohort. The researchers then calculated risk scores using the PLCOm2012 model. In the screening cohort, more Black patients than white patients were in high-risk groups, indicating that Black patients in this cohort had a higher risk of developing lung cancer.

As anticipated, white patients with screen-detected lung cancer generally had high lung cancer risk scores. "Among Black patients, we would have expected to see a similar trend," explains Dr. Barta. "However, we saw that despite having a lung cancer diagnosis through screening, Black patients were actually defined as lower risk. This indicates that the model is not accurately predicting risk of lung cancer in Black patients."

"These findings allowed us to identify weaknesses in this model for risk calculation for lung cancer," explains Shusted. "It indicates that we need to not only expand criteria for lung cancer screening so that more diverse populations are included, but that these prediction models need to include factors, like environmental contributors, access to health care, and other social determinants of health."

The researchers hope to continue building on these findings, with the ultimate goal of defining comprehensive risk factors and improving lung cancer screening uptake and adherence especially among vulnerable populations.

"This work is an important step to reducing disparities in the screening and early detection of lung cancer, and making sure we can trust our models to predict those individuals at the highest risk," says Dr. Barta.

Researchers at AMBER, the SFI Centre for Advanced Materials and BioEngineering Research, and from Trinity's School of Physics, have developed next-generation, graphene-based sensing technology using their innovative G-Putty material.

The team's printed sensors are 50 times more sensitive than the industry standard and outperform other comparable nano-enabled sensors in an important metric seen as a game-changer in the industry: flexibility.

Maximising sensitivity and flexibility without reducing performance makes the teams' technology an ideal candidate for the emerging areas of wearable electronics and medical diagnostic devices.

The team - led by Professor Jonathan Coleman from Trinity's School of Physics, one of the world's leading nanoscientists - demonstrated that they can produce a low-cost, printed, graphene nanocomposite strain sensor.

They developed a method to formulate G?putty?based inks that can be printed as a thin-film onto elastic substrates, including band-aids, and attached easily to the skin.

The team developed a method to formulate G?putty?based inks that can be printed as a thin-film onto elastic substrates, including band-aids, and attached easily to the skin.

Creating and testing inks of different viscosities (runniness) the team found that they could tailor G-Putty inks according to printing technology and application.

They published their results in the journal Small.

In medical settings, strain sensors are a highly valuable diagnostic tool used to measure changes in mechanical strain such as pulse rate, or the changes in a stroke victim's ability to swallow. A strain sensor works by detecting this mechanical change and converting it into a proportional electrical signal, thereby acting as mechanical-electrical converter.

While strain sensors are currently available on the market they are mostly made from metal foil that poses limitations in terms wearability, versatility, and sensitivity.

Professor Coleman said:

"My team and I have previously created nanocomposites of graphene with polymers like those found in rubberbands and silly putty. We have now turned G-putty, our highly malleable graphene blended silly putty, into an ink blend that has excellent mechanical and electrical properties. Our inks have the advantage that they can be turned into a working device using industrial printing methods, from screen printing, to aerosol and mechanical deposition.

"An additional benefit of our very low cost system is that we can control a variety of different parameters during the manufacturing process, which gives us the ability to tune the sensitivity of our material for specific applications calling for detection of really minute strains."

Current market trends in the global medical device market indicate that this research is well placed within the move to personalised, tuneable, wearable sensors that can easily be incorporated into clothing or worn on skin.

In 2020 the wearable medical device market was valued at USD $16 billion with expectations for significant growth particularly in remote patient monitoring devices and an increasing focus on fitness and lifestyle monitoring.

The team is ambitious in translating the scientific work into product. Dr Daniel O'Driscoll, Trinity's School of Physics, added:

"The development of these sensors represents a considerable step forward for the area of wearable diagnostic devices - devices which can be printed in custom patterns and comfortably mounted to a patient's skin to monitor a range of different biological processes.

"We're currently exploring applications to monitor real-time breathing and pulse, joint motion and gait, and early labour in pregnancy. Because our sensors combine high sensitivity, stability and a large sensing range with the ability to print bespoke patterns onto flexible, wearable substrates, we can tailor the sensor to the application. The methods used to produce these devices are low cost and easily scalable - essential criteria for producing a diagnostic device for wide scale use."

Professor Coleman was recently awarded a European Research Council Proof of Concept grant to build on these results to begin to develop a prototype for a commercial product. The ultimate aim of the group is identify potential investors and industry partners, and form a spin-out around the technology focusing on both recreational and medical applications.

A state of the art plenary session during the Pediatric Academic Societies (PAS) 2021 Virtual Meeting will bring together national experts on child poverty, racism and racial inequities, immigrant health, Native American culture, and environmental threats to discuss the intersectionality of child poverty.

Poor children do not just suffer from double jeopardy, but frequently multiple jeopardy from many overlapping threats to their health and development. The COVID-19 pandemic has further unearthed and intensified these threats to children including loss of financial resources, loss of nutritional supports, loss of family members, and loss of educational opportunity.

"Children are the poorest age group in our society," said Benard P. Dreyer, MD, FAAP. "On the hopeful side, we seem to be finally recognizing that the nation needs to address this issue, and with the passage of the reformed Child Tax Credit in March, there is hope that the level of poverty for children will be reduced by 40% this year. We have invited a powerhouse group of researchers and advocates to discuss the issue of child poverty and its intersection with racism, the issues of Native American children and families, as well as experts on environmental justice and primary care designed to address the needs of poor children."

Speakers will elucidate and contextualize the living Venn diagram of these intersections for children and families. They will also address the specific impact of the COVID-19 pandemic on these families who are vulnerable because of being under-resourced and often marginalized, and will leave the attendees with what is a call for action to all of us.

Presentations include:

The intersection of race and poverty: addressing health care inequities in children; presenter: Tumaini R. Coker, MD, MBA - University of Washington/Seattle Children's

Structural racism in medicine, poverty, and child population health; presenter: Nia J. Heard-Garris, MD, MSc - Ann & Robert H. Lurie Children's Hospital of Chicago/Northwestern University Feinberg College of Medicine

Native American communities, poverty, and child health; presenter: Shaquita Bell, MD - University of Washington School of Medicine, Department of Pediatrics

Environmental threats to poor children and the triple threat of environmental toxins, poverty, and racism; presenter: Mona Hanna-Attisha, MD, MPH - Michigan State University

Dr. Dreyer and Adam Schickedanz, MD, PhD, will chair the plenary, "The Intersection of Child Poverty With Race, Immigrant Status, and Environmental Threats in the Age of COVID-19," on Tuesday, May 4 at 5:30 p.m. EDT. Reporters interested in an interview with the presenters should contact PAS2021@piercom.com.

The PAS Meeting connects thousands of pediatricians and other health care providers worldwide. For more information about the PAS Meeting, please visit http://www.pas-meeting.org.

Next-generation gene sequencing (NGS) technologies --in which millions of DNA molecules are simultaneously but individually analyzed-- theoretically provides researchers and clinicians the ability to noninvasively identify mutations in the blood stream. Identifying such mutations enables earlier diagnosis of cancer and can inform treatment decisions. Johns Hopkins Kimmel Cancer Center researchers developed a new technology to overcome the inefficiencies and high error rates common among next-generation sequencing techniques that have previously limited their clinical application.

To correct for these sequencing errors, the research team from the Ludwig Center and Lustgarten Laboratory at the Johns Hopkins Kimmel Cancer Center developed SaferSeqS (Safer Sequencing System), a major improvement to widely used technologies based on a previous technology called SafeSeqS (Safe Sequencing System) that Hopkins investigators invented a decade ago. The new SaferSeqS technology detects rare mutations in blood in a highly efficient manner and reduces the error rate of commonly used technologies for evaluating mutations in the blood more than 100-fold.

Their findings were reported May 3 in Nature Biotechnology.

The presence of a mutation in a clinical sample could be an early indicator that a person has developed cancer, says study lead author and M.D./Ph.D. candidate Joshua Cohen. Cancer is a genetic disease, driven by oncogenes and tumor suppressor genes. A small portion of cancer cells shed their DNA into the bloodstream, allowing their mutations to be detected via blood sample. Detecting such mutations in blood rather through surgical biopsy of a cancerous tissue is called "a liquid biopsy." Such blood-based tests have the potential to detect cancer at an earlier stage, when it can be put into remission by surgery and/or chemotherapy. The challenge, Cohen explains, is that the vast majority of DNA present in the blood sample is shed by noncancer cells, and only a tiny fraction of the DNA is derived from the tumor. In patients with relatively early-stage cancers, a 10 mL blood sample will only contain a handful of molecules with a mutation.

"To detect cancers when they have the best chance of being cured requires a detection method that will pick up cancer signals that are present at extremely low frequencies," says Cohen. "The technical challenge in detecting these mutations is akin to finding a needle in a haystack."

The researchers addressed this challenge, with SaferSeqS, by efficiently tagging both strands of each original molecule present in an individual's blood with a unique barcode. It required new biochemical approaches to do this in an efficient manner with the small number of degraded DNA molecules that are usually present in blood. The investigators use the structural redundancy of the double-stranded DNA molecule to distinguish real mutations from errors, an approach called duplex sequencing. If both strands of a DNA molecule contain the identical mutation, it is far more likely that it is a real mutation and not an error.

"What makes SaferSeqS unique is the efficient tagging of both strands of the majority of DNA molecules circulating in the blood, the low error rate achieved through analysis of both strands of these DNA molecules, and the manner in which the molecules of interest are enriched prior to sequencing. Altogether, these advancements underlie the power of the new technology," says Cohen.

"Every molecule is sacred because it has the potential to be the one with the mutation we're looking for," says Cohen. "Because the absolute number of molecules is low, the technology has to be highly efficient at capturing each molecule to sensitively identify mutations."

To test the specificity and sensitivity of SaferSeqS in a clinically relevant setting, the researchers compared the samples to previous results from the CancerSEEK test, a single blood test that screens for eight common cancer types, developed and reported by the same research team (Science, 2018).

The researchers revisited 74 blood samples from patients with cancer that had false negative results -- undetectable mutations -- in the 2018 CancerSEEK study using SafeSeqS. In their newest study describing SaferSeqS, the researchers reassessed these blood samples. Using SaferSeqS, they observed a marked improvement in sensitivity, finding previously undetectable mutations in 68% of the samples tested.

"The SaferSeqS strategy affords highly reliable technical specificity, which translates to a better way to provide clinically meaningful results for patients with relatively early-stage and small tumors," says Cohen.

Taking these results together, the researchers conclude that SaferSeqS is highly sensitive and specific for detecting extremely rare cancer-related mutations, is potentially efficient and cost effective for clinical use, and reduces the error rate of existing mutation-detection approaches more than 100-fold.

The next step, they say, is to validate the results and demonstrate the clinical usefulness of the technology in prospective clinical trials.

The researchers say SaferSeqS will be the underlying platform for future CancerSEEK studies.

The most complete picture yet is coming into focus of how antibodies produced in people who effectively fight off SARS-CoV-2 work to neutralize the part of the virus responsible for causing infection. In the journal Science, researchers at The University of Texas at Austin describe the finding, which represents good news for designing the next generation of vaccines to protect against variants of the virus or future emerging coronaviruses.

Previous research focused on one group of antibodies that target the most obvious part of the coronavirus's spike protein, called the receptor-binding domain (RBD). Because the RBD is the part of the spike that attaches directly to human cells and enables the virus to infect them, it was rightly assumed to be a primary target of the immune system. But, testing blood plasma samples from four people who recovered from SARS-CoV-2 infections, the researchers found that most of the antibodies circulating in the blood -- on average, about 84% -- target areas of the viral spike protein outside the RBD -- and, apparently, for good reason.

"We found these antibodies are painting the entire spike, both the arc and the stalk of the spike protein, which looks a bit like an umbrella," said co-corresponding author Greg Ippolito, who is a research associate professor in UT Austin's Department of Molecular Biosciences and an assistant professor of oncology at the university's Dell Medical School. "The immune system sees the entire spike and tries to neutralize it."

Many of these non-RBD-directed antibodies the team identified act as a potent weapon against the virus by targeting a region in a part of the spike protein located in what would be the umbrella's canopy called the N-terminal domain (NTD). These antibodies neutralize the virus in cell cultures and were shown to prevent a lethal mouse-adapted version of the virus from infecting mice.

The NTD is also a part of the viral spike protein that mutates frequently, especially in several variants of concern. This suggests that one reason these variants are so effective at evading our immune systems is that they can mutate around one of the most common and potent types of antibody in our arsenals.

"There's an evolutionary arms race going on between the virus and our immune systems," said Jason Lavinder, research associate in the McKetta Department of Chemical Engineering and co-corresponding author of the new study. "We're all developing a standard immune response to this virus that includes targeting this one spot and that's exerting selective pressure on the virus. But then the virus is also exerting its evolutionary strength by trying to change around our selective immune pressures."

Despite these maneuvers by SARS-CoV-2, the researchers said about 40% of the circulating antibodies target the stalk of the spike protein, called the S2 subunit, which is also a part that the virus does not seem able to change easily.

"That's reassuring," Ippolito said. "That's an advantage our immune system has. It also means our current vaccines are eliciting antibodies targeting that S2 subunit, which are likely providing another layer of protection against the virus."

That's also good news for designing vaccine boosters or next-generation vaccines against variants of concern, and even for developing a vaccine that can protect against future pandemics from other strains of the coronavirus.

"It means we have a strong rationale for developing next-generation SARS-CoV-2 vaccines or even a pan-coronavirus vaccine that targets every strain," Ippolito said.

UT Austin researchers are among several in the world now aiming to develop a single coronavirus vaccine to fight infection from all coronaviruses, not just SARS-CoV-2.

BAR HARBOR, MAINE — Our kidneys are charged with the extraordinary task of filtering about 53 gallons of fluid a day, a process that depends on podocytes, tiny, highly specialized cells in the cluster of blood vessels in the kidney where waste is filtered that are highly vulnerable to damage.

In research at the MDI Biological Laboratory in Bar Harbor, Maine, a team led by Iain Drummond, Ph.D., director of the Kathryn W. Davis Center for Regenerative Biology and Aging, has identified the signaling mechanisms underlying podocyte formation, or morphogenesis. The discovery opens the door to the development of therapies to stimulate the regeneration of these cells, which are vital to ridding the body of toxins.

“Podocytes play a very important role in kidney function,” said Hermann Haller, M.D., president of the MDI Biological Laboratory and a nephrologist who leads the department of nephrology and hypertension at Hannover Medical School in Hanover, Germany. “The discovery of the signaling underlying podocyte morphogenesis by a team led by Iain Drummond is a major stride forward in the treatment of kidney disease.”

The study, entitled “Autonomous Calcium Signaling in Human and Zebrafish Podocytes Controls Kidney Filtration Barrier Morphogenesis,” was recently published in the Journal of the American Society of Nephrology.

In addition to Drummond, authors include Melissa Little, Ph.D., Aude Dorison, Ph.D., Irene Ghobrial and Alejandro Hidalgo-Gonzalez, Ph.D., all of The Royal Children’s Hospital, Murdoch Children’s Research Institute in Melbourne, Australia; Heiko Schenk, M.D., and Jan Hegermann of Hannover Medical School, Hanover, Germany; and Lynne Staggs of Hannover Medical School and the MDI Biological Laboratory.

The discovery of the signaling mechanism underlying podocyte formation is relevant to the treatment of a range of kidney conditions that can damage the glomerular filtration barrier, including acute kidney injury, developmental defects, premature birth defects, kidney cancer, polycystic kidney disease and chronic kidney disease (CDK) caused by diabetes or hypertension.

A major public health threat

In recent years, CDK has emerged as a major public health threat, especially among those age 60 and over, due to diabetes, hypertension and cardiovascular disease, all of which can contribute to kidney damage and all of which are increasing due to the aging of the world’s population. Approximately 38 million Americans, or 15 percent of the adult population, is estimated to have kidney disease.

When kidneys fail, the usual treatment is dialysis, an expensive, time-consuming procedure in which the blood is cleansed by an external filtering device. Though transplantation is another option, only a fraction of the tens of thousands of end-stage renal disease patients waiting for a kidney transplant receive one because the number of organ donors is insufficient to meet demand.

As a result of the limited options, kidney research at the MDI Biological Laboratory has focused on the regeneration of kidney tissue, and especially of nephrons, the functional units of the kidney, which include the glomerulus, in which the work of filtering the blood takes place. The approximately 1 million glomeruli in the body filter excess fluid and waste products from the blood, preventing the build-up of toxic waste.

The membrane of the glomerulus is lined with podocytes, whose interdigitated, foot-like projections (podo is Latin for “having a foot”) extend into the glomerular space. The podocytes are connected by a thin, mesh-like web called a “slit diaphragm” that functions as the final filtration barrier before fluid enters the glomerular space, from which it passes into collecting tubules and is ultimately excreted as urine.

“Podocytes are complex, which increases their vulnerability to injury,” Drummond explained. “There are many moving parts that have to come together just right in order to create the filtration barrier, and defects in any one of these can lead to disease. The more we know about how the individual parts and processes work together, the more targets we have for potential therapeutic interventions.”

In in vivo studies in zebrafish embryos and in vitro studies in maturing human kidney organoids, which are stem cell-derived “organs in a dish,” Drummond and his colleagues have discovered that calcium signaling is required for the formation of the podocyte foot process and slit diaphragm. The discovery supports the critical role of calcium signaling in the formation of the filtration barrier.

The discovery was enabled by a genetically encoded, green fluorescent calcium biosensor, GCaMP, that can be targeted to specific cell types. Because it lights up when calcium signaling is active, the biosensor allows scientists to image calcium signaling in the podocytes of transparent zebrafish embryos in real time under a fluorescence microscope to determine how they are made and what goes wrong during disease.

The zebrafish as a model for human disease

An important outcome of Drummond’s research is the establishment of the zebrafish as a model for human glomerular development and disease. The functional equivalency of podocytes in zebrafish and in human organoids suggests that their role has been conserved through evolution, thus validating the relevance of the zebrafish as a vertebrate model and as a screening platform for new therapies.

The research also identifies new routes for promoting kidney regeneration in humans. Unlike humans, zebrafish regenerate glomeruli throughout their adult lives. Though it is unknown if the signaling mechanisms employed during development are recapitulated during regeneration, Drummond thinks this is likely, in which case a deeper understanding could lead to therapies to trigger regeneration in humans.

“We wanted to go beyond looking at the shape and size and movement of cells during the process of forming the filter to the signals they are passing to generate this complex filter architecture,” Drummond said. “Once we understand these signals, we can accelerate tissue formation by promoting productive regenerative communication though our own messages in the form of signaling molecules.”

In recent years, the MDI Biological Laboratory has become a hub for kidney regeneration research due to its participation in a National Institutes of Health (NIH)-funded consortium, (Re)Building a Kidney (RBK), the aim of which is to develop a biological artificial kidney. The discovery of the signaling mechanism underlying podocyte formation will play a critical role in generating replacement kidney tissue.

In making his discovery, Drummond is building on the MDI Biological Laboratory’s distinguished historical reputation in kidney physiology. Much of what is known today about human kidney function was discovered at the MDI Biological Laboratory in the 20th century through comparative biological studies.

Biological organisms (such as elephant trunks, octopus tentacles, and human tongues) show remarkable dexterity and self-adaptation in unstructured environments, relying on the multiple-mode actuations of the skeleton-free muscular hydrostats. In general, muscular hydrostats mainly consist of well-ranged active 3D muscle-fiber arrays bundled by passive connective tissues (Fig. 1A). By selectively actuating the active 3D muscle-fiber arrays, muscular hydrostats can generate elongation, bending, contraction and twisting. Producing such multiple-mode actuation of muscular hydrostats is an interesting but long-lasting challenge in the field of robotics.

During past decades, many artificial muscles (such as dielectric elastomer actuators, pneumatic elastomer actuators, shape memory alloy/polymers) have been well developed to generate various actuations, which have been widely used in soft robotic systems. However, existed artificial muscles usually suffer from single actuation mode, such as elongation, bending, contraction, or twisting. Therefore, the development of artificial muscles with multiple-mode actuations remains elusive.

To address this challenge, inspired by the 3D muscle-fiber arrays in muscular hydrostats, a group from Shanghai Jiao Tong University, led by Professors Guoying Gu and Xiangyang Zhu, reported a class of multiple-mode pneumatic artificial muscles, called MAIPAMs, that are capable of multiple-mode actuations, like muscular hydrostats. The MAIPAMs mainly consist of active 3D elastomer-balloon arrays bundled by a passive elastomer membrane (Fig. 1B). When the compressed air is applied, each active elastomer balloon can generate an elongation while the passive elastomer membrane can transform the elongation into multiple-mode actuations, including elongation, bending, and spiraling (Fig. 1C). For the design and fabrication, a planar design and one-step rolling fabrication approach (Fig. 1D-E) is proposed to build the active 3D elastomer-balloon arrays of the MAIPAMs. In this sense, different MAIPAMs can be created to achieve complex actuation modes, such as parallel elongation-bending-spiraling actuations, parallel 10 bending actuations for omnidirectionally recording videos in a confined space, and cascaded elongation-bending-spiraling actuations for gripping. Owing to the scalable advantages of the planar design and rolling fabrication approach, MAIPAMs can also integrate limiting layers for contraction and twisting actuation modes, or compliant electrodes for self-sensing. They finally demonstrate that the MAIPAMs shows promising potentials in the field of soft robotics, such as detecting environments, manipulating or gripping objects, and climbing inside a pipe-line.

A Pediatric Policy Council state of the art plenary session during the Pediatric Academic Societies (PAS) 2021 Virtual Meeting explored the role of public health research in iterative policymaking to reduce gun violence in America.

The toll of gun violence on young people represents one of the most significant public health challenges facing contemporary America. In recent years, firearm-related injury and death has made headlines routinely, including mass shootings at schools, public festivals, and places of worship, while daily occurrences of gun violence affect local communities.

Gun violence touches young people directly, impacting them, their family members and friends. Additionally, the ongoing threat of gun violence, reinforced through regular active shooter drills in schools and media reports, extends the detrimental effects of gun violence further through biological stress mechanisms.

Despite the frequency of these tragic events, too little research into interventions and public policies to reduce gun violence has been conducted in over two decades due in large part to a reticence on the part of the federal government to fund such work.

In 2019, the Pediatric Policy Council engaged in successful advocacy efforts that helped to appropriate $25 million to the Centers for Disease Control and Prevention (CDC) and the National Institutes of Health (NIH) to administer grants for firearm research. Still, the U.S. has lagged behind its peers in identifying and implementing policies to address this problem.

"I'm eager to speak candidly with our expert panel about the challenges of advocating for firearm policy and the unique position of pediatricians to engage in this critical work," said Shale Wong, MD, MSPH. "Our president has charged Congress to act. Together with the power of youth advocates, we must garner the energy, confidence and perseverance to put our children first and decrease access to firearms. Our actions can save lives."

Presentations included:

Policies that work to reduce gun violence; presenter: Joshua Sharfstein, MD - Johns Hopkins Bloomberg School of Public Health

Research and evidence to reduce firearm injuries; presenter: Lois Lee, MD, MPH - Boston Children's Hospital/Harvard Medical School

Role of physician advocacy for gun violence prevention; presenter: Benjamin Hoffman, MD - OHSU

Dr. Wong and Shetal Shah, MD, chaired the session, "The Role of Research in Reducing Gun Violence: A Pediatric Policy Council State of the Art Plenary," on Sunday, May 2 at 10 a.m. EDT. Reporters interested in an interview with the presenters should contact PAS2021@piercom.com.

The PAS Meeting connects thousands of pediatricians and other health care providers worldwide. For more information about the PAS Meeting, please visit http://www.pas-meeting.org.

Researchers at University of California San Diego School of Medicine, with colleagues elsewhere, have used gene therapy to prevent learning and memory loss in a mouse model of Alzheimer's disease (AD), a key step toward eventually testing the approach in humans with the neurodegenerative disease.

The findings are published online in advance of the June 11, 2021 issue of Molecular Therapy-Methods & Clinical Development.

AD is characterized by the accumulation of clumps of misfolded proteins called amyloid plaques and neurofibrillary tau tangles, both of which impair cell signaling and promote neuronal death. Current AD treatments targeting plaques and tangles address only symptoms, which the study's authors say suggests a reversal and cure of AD will likely require a combination of interventional approaches that both decrease aggregating toxins and promote neuronal and synaptic plasticity.

Gene therapy is based on the premise that introducing a therapeutic compound to a precisely targeted region of the brain may restore or protect normal neural function and/or reverse neurodegenerative processes. In this case, researchers used a harmless adeno-associated viral vector to introduce synapsin-Caveolin-1 cDNA (AAV-SynCav1) into the hippocampus region of three-month-old transgenic AD mice.

The mice had been genetically modified to exhibit learning and memory deficits at 9 and 11 months, respectively. These deficits are associated with decreased expression of Caveolin-1, a scaffolding protein that builds the membranes housing cellular signaling tools, such as neurotrophin receptors that receive the critical extracellular signals, which govern all cellular life and function. With decay and destruction of these membranes, cell dysfunction and neurodegeneration follow.

"Our goal was to test whether SynCav1 gene therapy in these AD mouse models might preserve neuronal and synaptic plasticity in targeted parts of the membrane, and improve higher brain function," said senior author Brian P. Head, PhD, adjunct professor in the Department of Anesthesiology at UC San Diego School of Medicine and research health scientist at the VA San Diego Healthcare System.

And, in fact, that's what happened after mice received a single injection of AAV-SynCav1 to their hippocampus, which is a complex region deep within the brain that plays a major role in learning and memory. In AD, the hippocampus is among the first areas of the brain to be impaired.

At 9- and 11-months, said Head, hippocampal learning and memory in the mice were preserved. Moreover, researchers found that critical membrane structures and associated neurotrophin receptors also remained intact. Furthermore, these neuroprotective effects from SynCav1 gene delivery occurred independent of reducing amyloid plaque depositions.

"These results suggest SynCav1 gene therapy is an attractive approach to restore brain plasticity and improve brain function in AD and potentially in other forms of neurodegeneration caused by unknown etiology," wrote the authors.

Head's laboratory is currently testing SynCav1 gene delivery in other AD models at symptomatic stages as well as in a mouse model of amyotrophic lateral sclerosis (Lou Gehrig's disease). He hopes to advance this work to human clinical trials soon.

During the next 10 years, an estimated half-million individuals in the U.S. with autism spectrum disorder (ASD) are expected to transition from adolescence to adulthood, according to the Centers for Disease Control and Prevention.

That means thousands of these young adults will likely fall into a widening and potentially devastating gap in a variety of services--because they're too old for high school, but may not qualify for Medicaid-funded services, social work researchers at Case Western Reserve University predict in a new study.

The team of researchers from the Jack, Joseph and Morton Mandel School of Applied Social Sciences interviewed 174 families from Northeast Ohio to examine the use of health, medical and social services for youth with autism--from 16 to 30 years old--and their family caregivers. The study was funded by the International Center for Autism Research and Education (ICARE) through a Mt. Sinai Health Care Foundation catalytic grant and a grant from the Mandel School.

The findings, recently published in the Journal of Autism and Developmental Disorders, show that having a Medicaid waiver and high school enrollment emerged as "the most robust and consistent" predictors of youth with autism and their families using available services.

Those services include improved job training and access to medical care, speech and occupational therapy and transportation. Autism, a neurological condition typically diagnosed by age 3, often affects a person's communication abilities and social skills.

Having ample services available is vital, said Karen Ishler, a senior research associate at the Mandel School and the study's lead author.

"These findings provide a snapshot of the 'service cliff' faced by families and highlight the need for additional research," she said. "It reaffirms that once individuals leave high school, they are less likely to receive services. But having a Medicaid waiver provides a gateway to receiving all sorts of services."

David Biegel, the Henry L. Zucker Professor of Social Work Practice Emeritus at the Mandel School and a co-author of the study, noted that how states administer Medicaid waivers varies widely. Ohio has been generous in some regards, he said, but other states have done better for those with autism.

"Pennsylvania, for example, has a Medicaid waiver available specifically for those with autism," he said. "So when you apply, you don't have to compete with individuals with other health conditions."

Ishler said states like Ohio could take a lead role to address the issue, "but that also takes dollars and some motivation."

That would involve finding other options for funding services, changing eligibility requirements for Medicaid waivers and reducing the wait list, the researchers said. "Autism spectrum disorder affects the entire family," Biegel said.

"Many young people with ASD are at risk for reduced quality of life in adulthood," he said. "Additionally, families of adolescents and young adults with ASD face all kinds of stressors--especially during those critical, post-high school transition years."

Take, for example, finding a job. Students with autism are allowed to stay in Ohio public schools until age 22. When they finish, though, employment training and supports often dry up, according to the study.

It's something only made more challenging by the global COVID-19 pandemic.

"I think about some of these families, about how difficult it must be at home--especially for those whose youth have complex service needs," Ishler said.

ORLANDO, Fla. (May 3, 2021) - Researchers have identified a gene expressed in children with acute myeloid leukemia (AML) that could serve as a new immunotherapy treatment target, according to a new study published today in Blood Advances, a journal of the American Society of Hematology. The study, co-authored by researchers with Nemours Children's Health System, outlines the process and potential path for new immunotherapy drugs that improve survival and reduce treatment-related toxicity in children with AML.

Leukemia is the most common cancer in children and teens, and AML accounts for nearly one-fourth of those cases. AML is a fast-growing cancer that typically starts in immature bone marrow cells.

"Using genomic sequencing data, we identified novel targets for children's cancer and worked with collaborators to engineer new therapies for children with AML, rather than repurpose drugs from the adult cancer realm that don't work well in children," said E. Anders Kolb, MD, director of Nemours' Center for Childhood Cancer Research and a senior author of the study.

The researchers obtained genomic data from more than 2,000 pediatric patients with leukemia, to identify associated gene variants. Through genomic sequencing, they found that the gene mesothelin (MSLN) is abnormally expressed in more than one-third of childhood and young adult AML cases but was absent in normal bone marrow cells.

After this discovery, the researchers chose new immunotherapy drugs that would target MSLN to test in cell lines and animal models, to gauge pre-clinical effectiveness of leukemia therapies. Two experimental immunotherapy drugs were tested: anetumab ravtansine (Bayer), which is being tested in adult cancers, and a new compound, anti-MSLN-DGN462 (ImmunoGen). Each drug, in lab testing and in mouse models, produced potent destruction of leukemia cells. These drugs belong to a new class of cancer treatments known as anti-body drug conjugates (ADCs), which combine an antibody with a cancer-killing toxin. The antibody targets specific types of cancer cells and delivers the toxin directly to them, minimizing damage to healthy cells.

"We are working to show a proof of principle that we can create custom therapies for pediatric malignancies and turn the drugs we're testing in the lab into clinical trials," said Sonali P. Barwe, PhD, the study's co-lead author and head of the Preclinical Leukemia Testing Laboratory in Nemours' Center for Childhood Cancer Research.

The rapid evolution of genomic sequencing funded by the National Institutes of Health has led to the identification of new gene targets that are relevant for a significant number of patients. In addition, local organizations, such as the Leukemia Research Foundation of Delaware, have funded efforts like this study by Nemours to find new treatments.

Coronavirus (CoVs) infection in animals and humans is not new. The earliest papers in the scientific literature of coronavirus infection date to 1966. However, prior to SARS-CoV, MERS-CoV, and SARS-CoV-2, very little attention had been paid to coronaviruses.

Suddenly, coronaviruses changed everything we know about personal and public health, and societal and economic well-being. The change led to rushed analyses to understand the origins of coronaviruses in humans. This rush has led to a thus far fruitless search for intermediate hosts (e.g., civet in SARS-CoV and pangolin in SARS-CoV-2) rather than focusing on the important work, which has always been surveillance of SARS-like viruses in bats.

To clarify the origins of coronavirus' infections in humans, researchers from the Bioinformatics Research Center (BRC) at the University of North Carolina at Charlotte (UNC Charlotte) performed the largest and most comprehensive evolutionary analyses to date. The UNC Charlotte team analyzed over 2,000 genomes of diverse coronaviruses that infect humans or other animals.

"We wanted to conduct evolutionary analyses based on the most rigorous standards of the field," said Denis Jacob Machado, the first author of the paper. "We've seen rushed analyses that had different problems. For example, many analyses had poor sampling of viral diversity or placed excessive emphasis on overall similarity rather than on the characteristics shared due to common evolutionary history. It was very important to us to avoid those mistakes to produce a sound evolutionary hypothesis that could offer reliable information for future research."

The study's major conclusions are:

1) Bats have been ancestral hosts of human coronaviruses in the case of SARS-CoV and SARS-CoV-2. Bats also were the ancestral hosts of MERS-CoV infections in dromedary camels that spread rapidly to humans.

2) Transmission of MERS-CoV among camels and their herders evolved after the transmission from bats to these hosts. Similarly, there was transmission of SARS-CoV after the bat to human transmission among human vendors and their civets. These events are similar to the transmission of SARS-CoV-2 by fur farmers to their minks. The evolutionary analysis in this study helps to elucidate that these events occurred after the original human infection from lineages of coronaviruses hosted in bats. Therefore, these secondary transmissions to civet or mink did not play a role in the fundamental emergence of human coronaviruses.

3) The study corroborates the animal host origins of other human coronaviruses, such as HCoV-NL63 (from bat hosts), HCoV-229E (from camel hosts), HCoV-HKU1 (from rodent hosts) and HCoV-OC43 and HECV-4408 (from cow hosts).

4) Transmission of coronaviruses from animals to humans occurs episodically. From 1966 to 2020, the scientific community has described eight human-hosted lineages of coronaviruses. Although it is difficult to predict when a new human hosted coronavirus could emerge, the data indicate that we should prepare for that possibility.

"As coronavirus transmission from animal to human host occurs episodically at unpredictable intervals, it is not wise to attempt to time when we will experience the next human coronavirus," noted professor Daniel A. Janies, Carol Grotnes Belk Distinguished Professor of Bioinformatics and Genomics and team leader for the study. "We must conduct research on viruses that can be transferred from animals to humans on a continuous rather than reactionary basis."

Many miles of streams and rivers in the United States and elsewhere are polluted by toxic metals in acidic runoff draining from abandoned mining sites, and major investments have been made to clean up acid mine drainage at some sites. A new study based on long-term monitoring data from four sites in the western United States shows that cleanup efforts can allow affected streams to recover to near natural conditions within 10 to 15 years after the start of abatement work.

The four mining-impacted watersheds--located in mountain mining regions of California, Colorado, Idaho, and Montana--were all designated as Superfund sites under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA), which helps fund the cleanup of toxic-waste sites in the United States. They are among the few acid mine drainage sites where scientists have conducted extended studies to monitor the effectiveness of the remediation efforts.

"The good news from them all is that Superfund investments can restore the water quality and ecological health of the streams," said David Herbst, a research scientist at UC Santa Cruz and coauthor of a paper on the new findings to be published in the June issue of Freshwater Science. The paper is currently available online.

For the past two decades, Herbst has been monitoring streams affected by acid mine drainage from the Leviathan mine in the central Sierra Nevada. The new study developed out of discussions he had with other scientists involved in long-term studies of similar sites.

"There are not many of these long-term studies of impacted watersheds, and by combining our data we could identify the common threads of recovery between these different sites," Herbst said.

To assess the recovery of aquatic life in streams and rivers severely polluted by the abandoned mines, the researchers combined data from long-term monitoring over periods of 20 years or more. They used aquatic insects and other diverse invertebrate life (such as flatworms and snails) as indicators of the restoration of ecological health, with nearby unpolluted streams serving as standards for comparison.

Even with differing mixes of toxic metals and different treatment practices used to control the pollution at each site, the studies documented successful recovery to near natural conditions within 10 to 15 years. Much of the recovery was rapid, occurring within the first few years of treatment.

"These promising results and shared paths suggest that even daunting environmental problems can be remedied given the effort and investment," Herbst said.

The research also revealed that the sites shared common responses despite differences in the species of aquatic life occurring across this broad geographic region. Shared feeding habits, patterns of development, and behavioral characteristics unified how stream invertebrates responded to the alleviation of metal pollutants.

Species with traits such as feeding on algae, long life cycles, and clinging to the surfaces of stones became increasingly common as toxicity declined over time. Species that were more prevalent when metal concentrations were higher had traits such as rapid development, short life cycles, feeding on deposits of organic matter, and an ability to escape quickly off the bottom by drifting into the flow of water.

The species most sensitive to toxic metals are the mayflies, stoneflies, and caddisflies. Across all streams, the loss of these sensitive insects occurred at a toxicity level predicted by lab bioassays based on the combined levels of the toxic metals present.

"The convergence of these responses across streams and at a level consistent with how water quality criteria are established lends support to guidelines established for what chemical conditions are protective of stream and river ecosystems," Herbst said.

The additive toxicity of the metals present determined the response to pollutants, he noted, showing that water quality standards should be based on combined metals present rather than singly for each metal. In other words, even if a metal is below its toxic level, when it is present with other metals the combined effect may exceed the tolerance of aquatic life.

"It is vital to account for this factor in how water quality standards for metals are applied," Herbst said.

BOSTON -- Immunity often calls to mind the adaptive immune response, made up of antibodies and T cells that learn to fight specific pathogens after infection or vaccination. But the immune system also has an innate immune response, which uses a set number of techniques to provide a swift, non-specialized response against pathogens or support the adaptive immune response.

In the past few years, however, scientists have found that certain parts of the innate immune response can, in some instances, also be trained in response to infectious pathogens, such as HIV. Xu Yu, MD, a Core Member of the Ragon Institute of MGH, MIT and Harvard, and colleagues recently published a study in the Journal of Clinical Investigation which showed that elite controllers, a rare subset of people whose immune system can control HIV without the use of drugs, have myeloid dendritic cells, part of the innate immune response, that display traits of a trained innate immune cell.

"Using RNA-sequencing technology, we were able to identify one long-noncoding RNA called MIR4435-2HG that was present at a higher level in elite controllers' myeloid dendritic cells, which have enhanced immune and metabolic states," says Yu. "Our research shows that MIR4435-2HG might be an important driver of this enhanced state, indicating a trained response."

Myeloid dendritic cells' primary job is to support T cells, which are key to the elite controllers' ability to control HIV infection. Since MIR4435-2HG was found in higher levels only in cells from elite controllers, Yu explains, it may be part of a learned immune response to infection with HIV. Myeloid dendritic cells with increased MIR4435-2HG also had higher amounts of a protein called RPTOR, which drives metabolism. This increased metabolism may allow the myeloid dendritic cells to better support the T cells controlling the HIV infection.

"We used a novel sequencing technology, called CUT&RUN, to study the DNA of these cells," says postdoctoral fellow Ciputra Hartana, MD, PhD, the paper's first author. "It allowed us to study epigenetic modifications like MIR4435-2HG, which are molecules that bind to the DNA and change how, or if, the DNA is read by the cell's machinery."

The team found that MIR4435-2HG might work by attaching to the DNA near the location of the RPTOR gene. The bound MIR4435-2HG would then encourage the cell's machinery to make more of the RPTOR protein, using the instructions found in the RPTOR gene. This type of epigenetic modification, a trained response to HIV infection, would allow the myeloid dendritic cells to stay in an increased metabolic state and therefore provide long-term support to the T cells fighting the virus.

"Myeloid dendritic cells are very rare immune cells, accounting for only 0.1-0.3% of cells found in human blood," says Yu. "We were fortunate and thankful to have access to hundreds of millions of blood cells from the many study participants who have donated their blood to support our HIV research. These donations were key to making this discovery."

Understanding exactly how elite controllers' immune systems can control HIV is a key part of HIV cure research. If scientists can understand how elite controllers suppress this deadly virus, they may be able to develop treatments that allow other people living with HIV to replicate the same immune response, removing the need for daily medication to control the virus and achieving what is known as a functional cure.