Posts tagged with "rice university"

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New Report Underlines Importance of Science and Tech Funding

Investments in science and technology research are vital to the United States’ economic growth and global leadership, according to a new report from Rice University’s Baker Institute for Public Policy.

The Biden administration has made science and technology (S&T) a centerpiece of its early policy agenda with ambitious targets for federal investments in research and development (R&D). There are also growing concerns in Congress about the United States’ global leadership in S&T-focused industries, especially in relation to China.

“As the high technology sector (e.g., advanced computing and communications, social media platforms and other web-based services) becomes an increasingly large part of the overall U.S. economy, federal funding for early stage R&D, which has been at the root of much of the technological progress of this past century, is more important than ever,” wrote the Baker Institute’s Kenneth Evans, a scholar in science and technology policy, and Kirstin Matthews, a fellow in science and technology policy.

While President Biden’s first budget proposal aims to authorize historic increases to federal R&D agencies, the authors argue that significant challenges remain to ensure long-term, international competitiveness across scientific disciplines and advanced technologies.

According to their report, shifting priorities between administrations, changes to the ideology of Congress and broader economic conditions in the U.S. at large have resulted in inconsistent funding for R&D. 

“Traditionally, federal funding for R&D receives bipartisan support in Congress, particularly for health and defense-related research activities,” the authors wrote. “However, since the mid-1990s, government spending on basic research has declined or stagnated as a share of the U.S. GDP, in part due to the intrinsic uncertainties about the ultimate impacts of basic research.”

Science and technology R&D is essential to creating new knowledge and tools, the authors argue, because it ensures the development of new products and technologies that can drive domestic and global economies. Economists estimate innovations stemming from S&T accounted for more than 60% of economic growth over the last century. 

Yet scientists have placed relatively little value on evaluating and communicating the broader societal impacts of basic research to the public and especially to policymakers, the authors argue. The authors encourage researchers, especially academic scientists driven to action by anti-science rhetoric during the Trump administration, to continue to engage in public outreach during the Biden presidency. 

“Universities should encourage and incentivize avenues for public engagement through increased support of existing programs or funding new activities for interested faculty, postdocs, graduate students and research staff,” they wrote. 

“Building public support for R&D, strengthening trust in scientific institutions and expertise, and increasing scientists’ participation in decision-making related to S&T issues are critical to ensuring that scientific discoveries and innovation benefit the broader public and that increased investment in R&D serves the public interest,” they continued.

The report was a collaboration with two Rice undergraduate students and research interns in the science and technology policy program—Gabriella Hazan and Spoorthi Kamepalli.

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Rice Team Creates New Treatment for Diabetes

Rice University bioengineers are using 3D printing and smart biomaterials to create an insulin-producing implant for Type 1 diabetics.

 

The three-year project is a partnership between the laboratories of Omid Veiseh and Jordan Miller that’s supported by a grant from JDRF, the leading global funder of diabetes research. Veiseh and Miller will use insulin-producing beta cells made from human stem cells to create an implant that senses and regulates blood glucose levels by responding with the correct amount of insulin at a given time.

Veiseh, an assistant professor of bioengineering, has spent more than a decade developing biomaterials that protect implanted cell therapies from the immune system. Miller, an associate professor of bioengineering, has spent more than 15 years researching techniques to 3D print tissues with vasculature, or networks of blood vessels.

“If we really want to recapitulate what the pancreas normally does, we need vasculature,” Veiseh said. “And that’s the purpose of this grant with JDRF. The pancreas naturally has all these blood vessels, and cells are organized in particular ways in the pancreas. Jordan and I want to print in the same orientation that exists in nature.”

Type 1 diabetes is an autoimmune disease that causes the pancreas to stop producing insulin, the hormone that controls blood-sugar levels. About 1.6 million Americans live with Type 1 diabetes, and more than 100 cases are diagnosed each day. Type 1 diabetes can be managed with insulin injections. But balancing insulin intake with eating, exercise and other activities is difficult. Studies estimate that fewer than one-third of Type 1 diabetics in the U.S. consistently achieve target blood glucose levels.

Veiseh and Miller’s goal is to show their implants can properly regulate blood glucose levels of diabetic mice for at least six months. To do that, they’ll need to give their engineered beta cells the ability to respond to rapid changes in blood sugar levels.

“We must get implanted cells in close proximity to the bloodstream so beta cells can sense and respond quickly to changes in blood glucose,” Miller said. “We’re using a combination of pre-vascularization through advanced 3D bioprinting and host-mediated vascular remodeling to give each implant several shots at host integration.” 

The insulin-producing cells will be protected with a hydrogel formulation developed by Veiseh, who is also a Cancer Prevention and Research Institute of Texas Scholar. The hydrogel material, which has proven effective for encapsulating cell treatments in bead-sized spheres, has pores small enough to keep the cells inside from being attacked by the immune system but large enough to allow passage of nutrients and life-giving insulin.

“Blood vessels can go inside of them,” Veiseh said of the hydrogel compartments. “At the same time, we have our coating, our small molecules that prevent the body from rejecting the gel. So it should harmonize really well with the body.”

If the implant is too slow to respond to high or low blood sugar levels, the delay can produce a roller coaster-like effect, where insulin levels repeatedly rise and fall to dangerous levels.

“Addressing that delay is a huge problem in this field,” Veiseh said. “When you give the mouse, and ultimately a human, a glucose challenge that mimics eating a meal, how long does it take that information to reach our cells, and how quickly does the insulin come out?”

By incorporating blood vessels in their implant, he and Miller hope to allow their beta-cell tissues to behave in a way that more closely mimics the natural behavior of the pancreas.

Chrons via Rice University News for use by 360 Magazine

New Bacteria to Help Detect Inflammatory Bowel Diseases

In an important step toward the clinical application of synthetic biology, Rice University researchers have engineered a bacterium with the necessary capabilities for diagnosing inflammatory bowel diseases.

The engineered strain of the gut bacteria E. coli senses pH and glows when it encounters acidosis, an acidic condition that often occurs during flare ups of inflammatory bowel diseases like colitis, ileitis and Crohn’s disease.

Researchers at the University of Colorado (CU) School of Medicine used the Rice-created organism in a mouse model of Crohn’s disease to show acidosis activates a signature set of genes. The corresponding genetic signature in humans has previously been observed during active inflammation in Crohn’s disease patients. The results are available online in the Proceedings of the National Academy of Sciences.

Study co-author Jeffrey Tabor, an associate professor of bioengineering in Rice’s Brown School of Engineering, whose lab engineered the pH-sensing bacterium, said it could be reprogrammed to make colors that show up in the toilet instead of the fluorescent tags used in the CU School of Medicine experiments.

“We think it could be added to food and programmed to turn toilet water blue to warn patients when a flare up is just beginning,” said Tabor.

Bacteria have evolved countless specific and sensitive genetic circuits to sense their surroundings. Tabor and colleagues developed a biohacking toolkit that allows them to mix and match the inputs and outputs of these bacterial sensors. The pH-sensing circuit was discovered by Rice Ph.D. student Kathryn Brink in a 2019 demonstration of the plug-and-play toolkit.

PNAS study co-authors Sean Colgan, the director of the CU School of Medicine’s Mucosal Inflammation Program, and Ian Cartwright, a postdoctoral fellow in Colgan’s lab, read about the pH sensor and contacted Tabor to see if it could be adapted for use in a mouse model of Crohn’s disease.

“It turns out that measuring pH within the intestine through noninvasive ways is quite difficult,” said Colgan, the Levine-Kern Professor of Medicine and Immunology in the CU School of Medicine.

So Brink spent a few weeks splicing the necessary sensor circuits into an organism and sent it to Colgan’s lab.  

“Normally, the pH in your intestines is around seven, which is neutral, but you get a lot of inflammation in Crohn’s disease, and pH goes to something like three, which is very acidic,” Tabor said.

Colgan and colleagues have studied the genes that are turned on and off under such conditions and “needed a tool to measure pH in the intestine to show that the things they were observing in in vitro experiments were also really happening in a live animal,” Tabor said.

“Colonizing this bacterial strain was the perfect biological tool to monitor acidosis during active inflammation,” Colgan said. “Correlating intestinal gene expression with the bacterial pH sensing bacteria proved to be a useful and valuable set of biomarkers for active inflammation in the intestine.” 

Tabor said he believes the pH-sensing bacterium could potentially be advanced for human clinical trials in several years. 

Tabor’s work was supported by the Welch Foundation and the National Science Foundation.

Myotubes illustration by Heather Skovlund for 360 Magazine

Bio-inspired Muscle Growth

Bio-inspired scaffolds help promote muscle growth

Rice University bioengineers adapt extracellular matrix for electrospinning

Rice University bioengineers are fabricating and testing tunable electrospun scaffolds completely derived from decellularized skeletal muscle to promote the regeneration of injured skeletal muscle.

Their paper in Science Advances shows how natural extracellular matrix can be made to mimic native skeletal muscle and direct the alignment, growth and differentiation of myotubes, one of the building blocks of skeletal muscle. The bioactive scaffolds are made in the lab via electrospinning, a high-throughput process that can produce single micron-scale fibers.

The research could ease the burden of performing an estimated 4.5 million reconstructive surgeries per year to repair injuries suffered by civilians and military personnel.

Current methods of electrospinning decellularized muscle require a copolymer to aid in scaffold fabrication. The Rice process does not.

“The major innovation is the ability to prepare scaffolds that are 100% extracellular matrix,” said bioengineer and principal investigator Antonios Mikos of Rice’s Brown School of Engineering. “That’s very important because the matrix includes all the signaling motifs that are important for the formation of the particular tissue.”

The scaffolds leverage bioactive cues from decellularized muscle with the tunable material properties afforded through electrospinning to create a material rich with biochemical signals and highly specific topography. The material is designed to degrade as it is replaced by new muscle within the body.

Experiments revealed that cells proliferate best when the scaffolds are not saturated with a crosslinking agent, allowing them access to the biochemical cues within the scaffold matrix.

Electrospinning allowed the researchers to modulate crosslink density. They found that intermediate crosslinking led to better retention of fiber alignment during cell culture.

Most decellularized matrix for muscle regeneration comes from such thin membranes as skin or small intestine tissue. “But for muscle, because it’s thick and more complex, you have to cut it smaller than clinically relevant sizes and the original material properties are lost,” said Rice graduate student and lead author Mollie Smoak. “It doesn’t resemble the original material by the time you’re done.

“In our case, electrospinning was the key to make this material very tunable and have it resemble what it once was,” she said.

“It can generate fibers that are highly aligned, very similar to the architecture that one finds in skeletal muscle, and with all the biochemical cues needed to facilitate the creation of viable muscle tissue,” Mikos said.

Mikos said using natural materials rather than synthetic is important for another reason. “The presence of a synthetic material, and especially the degradation products, may have an adverse effect on the quality of tissue that is eventually formed,” he said.

“For eventual clinical application, we may use a skeletal muscle or matrix from an appropriate source because we’re able to very efficiently remove the DNA that may elicit an immune response,” Mikos said. “We believe that may make it suitable to translate the technology for humans.”

Smoak said the electrospinning process can produce muscle scaffolds in any size, limited only by the machinery.

“We’re fortunate to collaborate with a number of surgeons, and they see promise in this material being used for craniofacial muscle applications in addition to sports- or trauma-induced injuries to large muscles,” she said. “These would include the animation muscles in your face that are very fine and have very precise architectures and allow for things like facial expressions and chewing.”

Co-authors of the paper are Rice graduate student Katie Hogan and Jane Grande-Allen, the Isabel C. Cameron Professor of Bioengineering. Mikos is the Louis Calder Professor of Bioengineering and Chemical and Biomolecular Engineering.

The National Institutes of Health, the National Science Foundation and the Ford Foundation supported the research. 

Read the abtract here.

This news release can be found here.

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Rice University Study on Diabetes in Hispanic/Latino Adults

Wearable glucose monitors shed light on progression of Type 2 diabetes in Hispanic/Latino adults

Study by Sansum Diabetes Research Institute and Rice University points to new directions for improved diabetes care

In one of the first studies of its kind, medical and engineering researchers have shown wearable devices that continuously monitor blood sugar provide new insights into the progression of Type 2 diabetes among at-risk Hispanic/Latino adults.

The findings by researchers from Sansum Diabetes Research Institute (SDRI) and Rice University are available online this week in EClinicalMedicine, an open-access clinical journal published by The Lancet.

“The fresh look at the glucose data sheds new light on disease progression, which could have a direct impact on better management,” said Rice study co-author Ashutosh Sabharwal, professor and department chair in electrical and computer engineering and founder of Rice’s Scalable Health Labs. “An important aspect of our analysis is that the results are clinically interpretable and point to new directions for improved Type 2 diabetes care.”

The study builds on SDRI’s groundbreaking research to address Type 2 diabetes in underserved Hispanic/Latino communities. SDRI’s Farming for Life initiative assesses the physical and mental health benefits of providing medical prescriptions for locally sourced fresh vegetables to people with or at risk of Type 2 diabetes, with a focus on the Hispanic/Latino community. SDRI recently added a digital health technology called continuous glucose monitoring to this research.

Continuous glucose monitors track blood sugar levels around-the-clock and allow trends in blood glucose to be displayed and analyzed over time. The devices typically consist of two parts, a small electrode sensor affixed to the skin with an adhesive patch, and a receiver that gathers data from the sensor.

“We found that the use of this technology is both feasible and acceptable for this population, predominantly Mexican American adults,” said study co-author David Kerr, SDRI’s director of research and innovation. “The results also provided new insights into measurable differences in the glucose profiles for individuals at risk of as well as with noninsulin-treated Type 2 diabetes. These findings could facilitate novel therapeutic approaches to reduce the risk of progression of Type 2 diabetes for this underserved population.”

Sabharwal, who is also a co-investigator of the Precise Advanced Technologies and Health Systems for Underserved Populations (PATHS-UP) engineering research center, said, “The collaboration with SDRI aligns with our mission to use technology as an important building block to reduce health care disparities.”

“We are excited about the application of digital health technologies for underserved populations as a way to eliminate health disparities and improve health equity,” Kerr said. “This opens up potential for a larger number of collaborations to support SDRI’s evolving focus on precision nutrition and also the expanded use of digital health technologies for both the prevention and management of all forms of diabetes.”

Sabharwal is the Ernest Dell Butcher Professor of Engineering in Rice’s Brown School of Engineering.

Study co-authors include Souptik Barua of Rice and Namino Glantz, Casey Conneely, Arianna Larez and Wendy Bevier of SDRI.

The research was supported by the Department of Agriculture (2018-33800-28404), the National Science Foundation (1648451), the Hearst Foundation, the Mosher Foundation, Sun Life Financial, the St. Francis Foundation and the Blooming Prairie Foundation.

This release can be found online at Rice University’s website.

Follow Rice News and Media Relations via Twitter.

Located on a 300-acre forested campus in Houston, Rice University is consistently ranked among the nation’s top 20 universities by U.S. News & World Report. Rice has highly respected schools of Architecture, Business, Continuing Studies, Engineering, Humanities, Music, Natural Sciences and Social Sciences and is home to the Baker Institute for Public Policy. With 3,978 undergraduates and 3,192 graduate students, Rice’s undergraduate student-to-faculty ratio is just under 6-to-1. Its residential college system builds close-knit communities and lifelong friendships, just one reason why Rice is ranked No. 1 for lots of race/class interaction and No. 1 for quality of life by the Princeton Review. Rice is also rated as a best value among private universities by Kiplinger’s Personal Finance.

 

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Houston Methodist × Rice University

Houston Methodist, Rice U. launch neuroprosthetic collaboration


Center for Translational Neural Prosthetics and Interfaces to focus on restoring brain function after disease, injury

Neurosurgery’s history of cutting diseases out of the brain is morphing into a future in which implanting technology intothe brain may help restore function, movement, cognition and memory after patients suffer strokes, spinal cord injuries and other neurological disorders. Rice University and Houston Methodist have forged a partnership to launch the Center for Translational Neural Prosthetics and Interfaces, a collaboration that brings together scientists, clinicians, engineers and surgeons to solve clinical problems with neurorobotics.  

“This will be an accelerator for discovery,” said center co-director Dr. Gavin Britz, chair of the Houston Methodist Department of Neurosurgery. “This center will be a human laboratory where all of us — neurosurgeons, neuroengineers, neurobiologists — can work together to solve biomedical problems in the brain and spinal cord. And it’s a collaboration that can finally offer some hope and options for the millions of people worldwide who suffer from brain diseases and injuries.”

Houston Methodist neurosurgeons, seven engineers from the Rice Neuroengineering Initiative and additional physicians and faculty from both institutions form the center’s core team. The center also plans to hire three additional engineers who will have joint appointments at Houston Methodist and Rice. Key focus areas include spinal cord injury, memory and epilepsy studies, and cortical motor/sensation conditions.

“The Rice Neuroengineering Initiative was formed with this type of partnership in mind,” said center co-director Behnaam Aazhang, Rice’s J.S. Abercrombie Professor of Electrical and Computer Engineering, who also directs the neuroengineering initiative, which launched in 2019 to bring together the brightest minds in neuroscience, engineering and related fields to improve lives by restoring and extending the capabilities of the human brain. “Several core members, myself included, have existing collaborations with our colleagues at Houston Methodist in the area of neural prosthetics. The creation of the Center for Translational Neural Prosthetics and Interfaces is an exciting development toward achieving our common goals.”

The physical space for the center’s operation includes more than 25,000 square feet of Rice Neuroengineering Initiative laboratories and experimental spaces in the university’s BioScience Research Collaborative, as well as an extensive build-out underway at Houston Methodist’s West Pavilion location that’s expected to be completed late this year. The Houston Methodist facility will include operating rooms and a human laboratory where ongoing patient/volunteer diagnosis and assessment, device fabrication and testing, and education and training opportunities are planned.

“This partnership is a perfect blend of talent,” said Rice’s Marcia O’Malley, a core member of both the new center and university initiative and the Thomas Michael Panos Family Professor in Mechanical Engineering. “We will be able to design studies to test the efficacy of inventions and therapies and rely on patients and volunteers who want to help us test our ideas. The possibilities are limitless.”

Houston Methodist neurobiologist Philip Horner describes the lab as “a merging of wetware with hardware,” where robotics, computers, electronic arrays and other technology — the hardware — is incorporated into the human brain or spinal cord — the wetware. The centerpiece of this working laboratory is a zero-gravity harness connected to a walking track, with cameras and sensors to record feedback, brain activity and other data.

While the Houston Methodist space is being built, collaborations already are underway between the two institutions, which sit across Main Street from one another in the Texas Medical Center. Among them are the following:

  • O’Malley and Houston Methodist’s Dr. Dimitry Sayenko, assistant professor of neurosurgery, will head the first pilot project involving the merging of two technologies to restore hand function following a spinal cord injury or stroke. O’Malley will pair the upper limb exoskeleton she invented with Sayenko’s noninvasive stimulator designed to wake up the spinal cord. Together, they hope these technologies will help patients achieve a more extensive recovery — and at a faster pace.
  • Rice neuroengineer Lan Luan, assistant professor of electrical and computer engineering, and Britz, a neurosurgeon, are collaborating on a study to measure the neurovascular response following a subarachnoid hemorrhage, a life-threatening stroke caused by bleeding just outside the brain. Two-thirds of people who suffer these brain bleeds either die or end up with permanent disabilities. Luan invented very small and flexible electrodes that can be implanted in the brain to measure, record and map its activities. Her work with mice could lead to human brain implants that may help patients recover from traumatic brain injuries caused by disease or accidents.
  • Aazhang, Britz and Taiyun Chi, assistant professor of electrical and computer engineering at Rice, are collaborating on the detection of mild traumatic brain injuries (mTBI) from multimodal observations and on alleviating mTBI using neuromodulations. This project is of particular interest to the Department of Defense.
Green covid by Mina Tocalini for 360 Magazine

Tuberculosis Bacteria Paradox

TB-causing bacteria remember prior stress, react quickly to new stress

Tuberculosis bacteria have evolved to remember stressful encounters and react quickly to future stress, according to a study by computational bioengineers at Rice University and infectious disease experts at Rutgers New Jersey Medical School (NJMS).

Published online in the open-access journal mSystems, the research identifies a genetic mechanism that allows the TB-causing bacterium, Mycobacterium tuberculosis, to respond to stress rapidly and in manner that is “history-dependent,” said corresponding author Oleg Igoshin, a professor of bioengineering at Rice.

Researchers have long suspected that the ability of TB bacteria to remain dormant, sometimes for decades, stems from their ability to behave based upon past experience.

Latent TB is an enormous global problem. While TB kills about 1.5 million people each year, the World Health Organization estimates that 2-3 billion people are infected with a dormant form of the TB bacterium.

“There’s some sort of peace treaty between the immune system and bacteria,” Igoshin said. “The bacteria don’t grow, and the immune system doesn’t kill them. But if people get immunocompromised due to malnutrition or AIDS, the bacteria can be reactivated.”

One of the most likely candidates for a genetic switch that can toggle TB bacteria into a dormant state is a regulatory network that is activated by the stress caused by immune cell attacks. The network responds by activating several dozen genes the bacteria use to survive the stress. Based on a Rice computational model, Igoshin and his longtime Rutgers NJMS collaborator Maria Laura Gennaro and colleagues predicted just such a switch in 2010. According to the theory, the switch contained an ultrasensitive control mechanism that worked in combination with multiple feedback loops to allow hysteresis, or history-dependent behavior.

“The idea is that if we expose cells to intermediate values of stress, starting from their happy state, they don’t have that much of a response,” Igoshin explained. “But if you stress them enough to stop their growth, and then reduce the stress level back to an intermediate level, they remain stressed. And even if you fully remove the stress, the gene expression pathway stays active, maintaining a base level of activity in case the stress comes back.”

In later experiments, Gennaro’s team found no evidence of the predicted control mechanism in Mycobacterium smegmatis, a close relative of the TB bacterium. Since both organisms use the same regulatory network, it looked like the prediction was wrong. Finding out why took years of follow-up studies. Gennaro and Igoshin’s teams found that the TB bacterium, unlike their noninfectious cousins, had the hysteresis control mechanism, but it didn’t behave as expected.

“Hysteretic switches are known to be very slow, and this wasn’t,” Igoshin said. “There was hysteresis, a history-dependent response, to intermediate levels of stress. But when stress went from low to high or from high to low, the response was relatively fast. For this paper, we were trying to understand these somewhat contradictory results. ”

Igoshin and study co-author Satyajit Rao, a Rice doctoral student who graduated last year, revisited the 2010 model and considered how it might be modified to explain the paradox. Studies within the past decade had found a protein called DnaK played a role in activating the stress-response network. Based on what was known about DnaK, Igoshin and Rao added it to their model of the dormant-active switch.

“We didn’t discover it, but we proposed a particular mechanism for it that could explain the rapid, history-dependent switching we’d observed,” Igoshin said. “What happens is, when cells are stressed, their membranes get damaged, and they start accumulating unfolded proteins. Those unfolded proteins start competing for DnaK.”

DnaK was known to play the role of chaperone in helping rid cells of unfolded proteins, but it plays an additional role in the stress-response network by keeping its sensor protein in an inactive state.

“When there are too many unfolded proteins, DnaK has to let go of the sensor protein, which is an activation input for our network,” Igoshin said. “So once there are enough unfolded proteins to ‘distract’ DnaK, the organism responds to the stress.”

Gennaro and co-author Pratik Datta conducted experiments at NJMS to confirm DnaK behaved as predicted. But Igoshin said it is not clear how the findings might impact TB treatment or control strategies. For example, the switch responds to short-term biochemical changes inside the cell, and it’s unclear what connection, if any, it may have with long-term behaviors like TB latency, he said.

“The immediate first step is to really try and see whether this hysteresis is important during the infection,” Igoshin said. “Is it just a peculiar thing we see in our experiments, or is it really important for patient outcomes? Given that it is not seen in the noninfectious cousin of the TB bacterium, it is tempting to speculate it is related to survival inside the host.”

Gennaro is a professor of medicine and epidemiology at Rutgers Biomedical and Health Sciences. Igoshin is a senior investigator at Rice’s Center for Theoretical Biological Physics.

The research was supported by the Welch Foundation (C-1995) and the National Institutes of Health (GM096189, AI122309, AI104615, HL149450).

New Scientific Study by Rice University Biochemists

Michael Stern and James McNew (Photo by Jeff Fitlow/Rice University)

Study: Early, late stages of degenerative diseases are distinct
Two-phase theory applies to diseases like Alzheimer’s, Parkinson’s, muscle atrophy

Rice University biochemists Michael Stern and James McNew have studied how neurodegeneration kills cells. They’ve conducted countless experiments over more than a decade, and they’ve summarized all they’ve learned in a simple diagram they hope may change how doctors perceive and treat degenerative diseases as varied as Alzheimer’s, Parkinson’s, and muscle atrophy.

In a study published this month in Molecular Psychiatry, McNew and Stern propose that degeneration, at the cellular level, occurs in two distinct phases that are marked by very different activities of protein signaling pathways that regulate basic cell functions.

“We would like clinicians and other researchers to understand that the two phases of degeneration represent distinct entities, with distinct alterations in signaling pathways that have distinct effects on disease pathology,” said Stern, a professor of biosciences at Rice. “In other words, we think that patients need to be treated differently depending on which phase they are in.”

Stern and McNew’s diagram shows how the activity of key cell-signaling proteins either increases or decreases at the onset of degeneration, ultimately bringing about oxidative stress. Oxidative stress then brings about the second phase of the condition, during which degeneration occurs, where the signaling proteins implicated in the first phase behave in a completely different way.

Because cells behave quite differently in the two phases, the research suggests patients in different phases of a disease may respond differently to the same treatment.

“The two phases of degeneration haven’t been previously recognized, so it hasn’t been understood, clinically, that you have two different populations of patients,” McNew said. “Today, they’re treated like one population, and we think this has confounded clinical trials and explains why some trials on Alzheimer’s have given variable and irreproducible effects. It would be like trying to treat all meningitis patients with antibiotics without realizing that there are two types of meningitis, one bacterial and one viral.”

Stern and McNew, professors of biochemistry and cell biology in Rice’s Department of BioSciences, became interested in the cellular processes of neurodegenerative disorders when they began studying hereditary spastic paraplegia (HSP) in the late 2000s. A rare disorder, HSP is marked by numbness and weakness in the legs and feet due to the progressive deterioration of neurons that connect the spine and lower leg.

These are some of the longest cells in the body, and starting with clues about structural defects that could cause them to degenerate, McNew and Stern used experiments on fruit flies to systematically piece together the biochemical domino effect that caused the neurons to progressively lose more and more function and eventually die. It had been thought that nerve damage could lead to muscle atrophy, but their studies found that muscle cells attached to the neurons started degenerating from the same type of biochemical cascade before the nerve cells died.

A key player in the cascade was a protein called TOR, a master regulator of cell growth and an essential protein for all higher-order life from yeast to humans. TOR acts like a knob, dialing growth up or down to suit the conditions a cell is experiencing. In some conditions, high growth is warranted and beneficial, and in other situations, growth needs to be dialed back so energy and resources can be conserved for daily chores, like the recycling or repair that take place during a process known as autophagy.

Some cancers highjack TOR to promote aggressive cell growth, and increased TOR activity has also been implicated in neurodegenerative disorders like Alzheimer’s and Parkinson’s diseases and in diseases marked by muscle atrophy. After compiling evidence about how TOR and several other signaling proteins behaved in neurodegeneration, McNew and Stern won a grant from the National Institute of Neurological Disorders and Stroke in 2018 for experiments to investigate signaling pathway changes that occur in the early stages of degeneration.

“At the time, we thought there might be a late phase during which degeneration actually occurs, but we didn’t propose any experiments to test that,” Stern said. “In the new paper, we’re explicit about the existence of a late phase. We propose mechanistically why degeneration occurs only during this phase, and cite abundant research in support.”

Stern said the two-phase process described in the study “is the basic engine that drives most or even all forms of degeneration forward. However, in addition, there are also inputs whose role is to specify how fast the engine turns over.”

To understand neurodegeneration, it’s critical to understand how those inputs work, he said. For example, insulin resistance plays a well-known role in driving Alzheimer’s disease, and in the study, McNew and Stern describe how it does that by accelerating progression through the early phase.

“Similarly, our data suggests that decreases in synaptic transmission, as occurs in our HSP insect model, likewise triggers degeneration by accelerating progression through the early phase,” McNew said. “Our NIH grant was funded so that we could learn the mechanism by which that occurs.”

Now that they clearly understand that two phases of degeneration exist, Stern said he and McNew would like to carry out more experiments to see how the effects of specific genes on degeneration are altered when they are activated in the early and late phases.

“What we would like to do in the last two years of the grant is to obtain data to test some of the predictions we have made, which will help determine if the ideas we have presented are likely to be correct,” Stern said.

The research was supported by the National Institutes of Health (R01-NS102676).

Mina Tocalini, 360 Magazine, COVID-19

New Possible Key for Targeting Viruses

“Position 4” didn’t seem important until researchers took a long look at a particular peptide. That part of the peptide drawn from a SARS-CoV virus turned out to have an unexpected but significant influence on how it stably binds with a receptor central to the immune system’s ability to attack diseased cells. 

In a study published by the Proceedings of the National Academy of Sciences, researchers at Rice University’s Brown School of Engineering and the University of Texas MD Anderson Cancer Center revealed models at an atomic resolution that detail not only the binding but also, for the first time, the unbinding mechanisms that underlie a key component of the immune system. 

They say a better understanding of the entire mechanism could lead to advancements in immunotherapy that boost the body’s ability to fight disease. 

Rice computer scientist Lydia Kavraki, alumnus Jayvee Abella and postdoctoral researcher Dinler Antunes, led the study.

“Finding good targets to trigger a protective immune response is very challenging, especially in cancer research,” Antunes said. “The fact that this particular peptide was predicted not to bind to HLAs (human leukocyte antigens) by sequence-based methods highlights a blind spot in our current prediction capacity.”

“By incorporating structural analysis, we can detect the contribution of these secondary interactions to peptide binding and stability, hopefully enabling us to find better targets for antiviral vaccine development and T-cell-based cancer immunotherapy,” he said.

The researchers used their simulations to illuminate details of how the intracellular SARS peptide, QFKDNVILL, binds to an MHC receptor protein known as HLA-A24:02, primarily at dominant anchors on both ends of the peptide (at positions 2 and 9) and presents them for inspection to the immune system’s T cells. 

Stable binding of a peptide and MHC is a prerequisite to the activation of T cells, which look for peptides not normally found in healthy cells. If the peptide and protein don’t bind, the T cell is not prompted to attack. 

“That much was known from previous studies of the bound and unbound states of many such complexes,” Kavraki said. “What they didn’t capture was the intermediate states and the transitions that lead from one state to another, especially the unbinding.

“I think this is the only analysis that shows the unbinding of peptides from the MHC with atomic resolution,” Kavraki said. “Other peptides have similar characteristics and we think they would have similar behaviors.”

All of these interactions were revealed in great detail through Markov state models that analyze how systems change over time. In this case, the models revealed the importance of secondary sites that support the peptide’s primary anchors. That’s where position 4 stood out.

“There are the main, canonical anchors that people know, but there are these secondary interactions that contribute to the binding and the stability,” Antunes said. “These are harder to capture, but in this study, it seems that position 4 plays a very important role. When you mutate it, it affects the behavior of the peptide as it unbinds from the molecule.”

The researchers modeled mutations of the MHC to see how they would influence binding and found they supported the importance of position 4 to the stability of the complex.

“Our computational approach was able to make predictions on the effect of mutations that are then experimentally verified,” said co-author Cecilia Clementi, a former Rice professor who recently became Einstein Professor of Physics at the Free University of Berlin. 

The researchers developed a two-stage process to simplify the computational complexity of atom-scale analysis of large molecules. The first stage used a technique called umbrella sampling to accelerate the initial exploration of the molecules. The second, exploratory stage used adaptive sampling, in which simulations are driven to accelerate the construction of the Markov model.  

“The challenge is that these MHCs are pretty large systems for computational chemists to simulate,” said Abella, whose research on the topic formed much of his doctoral thesis. “We had to make some approximations and leverage advances in these classes of methods to move forward.”

“We’re not the first one to study unbinding, but what characterizes our work over others is that we keep full atomic resolution in our simulations,” he said. “Other works use a technique known as a Markov chain Monte Carlo, whereas we use molecular dynamics, which lets us incorporate time into our computation to capture the kinetics.”

Their methods can be applied to other peptide-MHC complexes with existing 3D models. “This was, in some sense, a feasibility study to show we can use molecular dynamics and build a Markov state model of a system this size,” Abella said. 

The researchers also noted the study’s relevance to the current fight against COVID-19, as the SARS peptide they viewed, QFKDNVILL, is highly similar to the NFKDQVILL peptide in SARS-CoV-2, with the same binding pockets in positions 2, 4 and 9.

“These results suggest that both peptides can bind to HLA-A*2402 and provide targets for anti-viral T-cell responses, which are of great interest in light of the current pandemic,” said co-author Gregory Lizée, a professor in the Department of Melanoma Medical Oncology at MD Anderson. “But these results also shed light on many other potential immune targets, including those of other viruses and even human cancers.”

Kavraki noted that experimental work by long-term collaborator Lizée and Kyle Jackson, a graduate research assistant at Lizée’s lab who produced the mutant proteins, were critical to validate their simulations. Kavraki’s own lab won a National Science Foundation (NSF) Rapid Response Research grant to help identify fragments of SARS-CoV-2 viral proteins as possible targets for vaccine development. 

Kavraki is the Noah Harding Professor of Computer Science and a professor of bioengineering, mechanical engineering and electrical and computer engineering. 

The Cancer Prevention and Research Institute of Texas, the Gulf Coast Consortia, the NSF, the Einstein Foundation Berlin and the Welch Foundation supported the research.

Loose Standards Undermined Research on COVID-19 Test Accuracy

The COVID-19 pandemic was met with a rush of research on the many factors related to the crisis, including the accuracy of different testing methods. However, many of the studies conducted in the early stages of the pandemic did not meet the usual rigorous scientific standards, according to researchers at Rice University and Baylor College of Medicine.

In “The estimation of diagnostic accuracy of tests for COVID-19: A scoping review,” which will appear in an upcoming edition of the Journal of Infection, authors Dierdre Axell-House, Richa Lavingia, Megan Rafferty, Eva Clark, E. Susan Amirian and Elizabeth Chiao found that better-designed studies are needed to appropriately evaluate the different types of COVID-19 tests.

They reviewed 49 articles published between Dec. 31, 2019, and June 19, 2020, that evaluated the validity of different types of coronavirus testing. These studies were assessed using elements of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) guidelines, which are used to evaluate if bias could be playing a role in the results of studies on diagnostic test accuracy.

Amirian, an epidemiologist at Rice’s Texas Policy Lab (TPL), said when it comes to conducting studies on testing accuracy, design is critically important. She said the major limitations found in the design of most of the studies they examined could lead to erroneous or misleading results.

“Without rigorous evaluations of which tests are the most accurate, it’s hard to know which tests are more likely to lead to false negatives, which could contribute to greater spread of the virus,” said Rafferty, a health data analyst at the TPL. “Although it’s difficult to say, some of the quality issues may have resulted from these studies being streamlined in response to the immediate need for timely information.”

“COVID-19 has now been a health crisis for nearly a year,” Amirian said. “With regard to research, the academic community needs to move away from being in acute emergency mode and think about how we’re going to handle this as a chronic crisis. When researchers are in emergency mode, we tend to be more open to sacrificing a lot of the strict quality standards for conducting research that we usually uphold.”

The paper is available online here.