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New Miniature Heart Could Help Speed Heart Disease Cures

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There’s no safe way to get a close-up view of the human heart as it goes about its work: you can’t just pop it out, take a look, then slot it back in. Scientists have tried different ways to get around this fundamental problem: they’ve hooked up cadaver hearts to machines to make them pump again, attached lab-grown heart tissues to springs to watch them expand and contract. Each approach has its flaws: reanimated hearts can only beat for a few hours; springs can’t replicate the forces at work on the real muscle. But getting a better understanding of this vital organ is urgent: in America, someone dies of heart disease every 36 seconds, according to the Centers for Disease Control and Prevention.

There’s no safe way to get a close-up view of the human heart as it goes about its work: you can’t just pop it out, take a look, then slot it back in. Scientists have tried different ways to get around this fundamental problem: they’ve hooked up cadaver hearts to machines to make them pump again, attached lab-grown heart tissues to springs to watch them expand and contract. Each approach has its flaws: reanimated hearts can only beat for a few hours; springs can’t replicate the forces at work on the real muscle. But getting a better understanding of this vital organ is urgent: in America, someone dies of heart disease every 36 seconds, according to the Centers for Disease Control and Prevention.

Now, an interdisciplinary team of engineers, biologists, and geneticists has developed a new way of studying the heart: they’ve built a miniature replica of a heart chamber from a combination of nanoengineered parts and human heart tissue. There are no springs or external power sources—like the real thing, it just beats by itself, driven by the live heart tissue grown from stem cells. The device could give researchers a more accurate view of how the organ works, allowing them to track how the heart grows in the embryo, study the impact of disease, and test the potential effectiveness and side effects of new treatments—all at zero risk to patients and without leaving a lab.

The Boston University–led team behind the gadget—nicknamed miniPUMP, and officially known as the cardiac miniaturized Precision-enabled Unidirectional Microfluidic Pump—says the technology could also pave the way for building lab-based versions of other organs, from lungs to kidneys. Their findings have been published in Science Advances.

“We can study disease progression in a way that hasn’t been possible before,” says Alice White, a BU College of Engineering professor and chair of mechanical engineering. “We chose to work on heart tissue because of its particularly complicated mechanics, but we showed that, when you take nanotechnology and marry it with tissue engineering, there’s potential for replicating this for multiple organs.”

According to the researchers, the device could eventually speed up the drug development process, making it faster and cheaper. Instead of spending millions—and possibly decades—moving a medicinal drug through the development pipeline only to see it fall at the final hurdle when tested in people, researchers could use the miniPUMP at the outset to better predict success or failure.

The project is part of CELL-MET, a multi-institutional National Science Foundation Engineering Research Center in Cellular Metamaterials that’s led by BU. The center’s goal is to regenerate diseased human heart tissue, building a community of scientists and industry experts to test new drugs and create artificial implantable patches for hearts damaged by heart attacks or disease.

“Heart disease is the number one cause of death in the United States, touching all of us,” says White, who was chief scientist at Alcatel-Lucent Bell Labs before joining BU in 2013. “Today, there is no cure for a heart attack. The vision of CELL-MET is to change this.”

Personalized Medicine

There’s a lot that can go wrong with your heart. When it’s firing properly on all four cylinders, the heart’s two top and two bottom chambers keep your blood flowing so that oxygen-rich blood circulates and feeds your body. But when disease strikes, the arteries that carry blood away from your heart can narrow or become blocked, valves can leak or malfunction, the heart muscle can thin or thicken, or electrical signals can short, causing too many—or too few—beats. Unchecked, heart disease can lead to discomfort—like breathlessness, fatigue, swelling, and chest pain—and, for many, death.

“The heart experiences complex forces as it pumps blood through our bodies,” says Christopher Chen, BU’s William F. Warren Distinguished Professor of Biomedical Engineering. “And while we know that heart muscle changes for the worse in response to abnormal forces—for example, due to high blood pressure or valve disease—it has been difficult to mimic and study these disease processes. This is why we wanted to build a miniaturized heart chamber.”

At just 3 square centimeters, the miniPUMP isn’t much bigger than a postage stamp. Built to act like a human heart ventricle—or muscular lower chamber—its custom-made components are fitted onto a thin piece of 3D-printed plastic. There are miniature acrylic valves, opening and closing to control the flow of liquid—water, in this case, rather than blood—and small tubes, funneling that fluid just like arteries and veins. And beating away in one corner, the muscle cells that make heart tissue contract, cardiomyocytes, made using stem cell technology.

“They’re generated using induced pluripotent stem cells,” says Christos Michas (ENG’21), a postdoctoral researcher who designed and led the development of the miniPUMP as part of his PhD thesis.

To make the cardiomyocyte, researchers take a cell from an adult—it could be a skin cell, blood cell, or just about any other cell—reprogram it into an embryonic-like stem cell, then transform that into the heart cell. In addition to giving the device literal heart, Michas says the cardiomyocytes also give the system enormous potential in helping pioneer personalized medicines. Researchers could place a diseased tissue in the device, for instance, then test a drug on that tissue and watch to see how its pumping ability is impacted.

“With this system, if I take cells from you, I can see how the drug would react in you, because these are your cells,” says Michas. “This system replicates better some of the function of the heart, but at the same time, gives us the flexibility of having different humans that it replicates. It’s a more predictive model to see what would happen in humans—without actually getting into humans.”

According to Michas, that could allow scientists to assess a new heart disease drug’s chances of success long before heading into clinical trials. Many drug candidates fail because of their adverse side effects.

“At the very beginning, when we’re still playing with cells, we can introduce these devices and have more accurate predictions of what will happen in clinical trials,” says Michas. “It will also mean that the drugs might have fewer side effects.”

Thinner than a Human Hair

One of the key parts of the miniPUMP is an acrylic scaffold that supports, and moves with, the heart tissue as it contracts. A series of superfine concentric spirals—thinner than a human hair—connected by horizontal rings, the scaffold looks like an artsy piston. It’s an essential piece of the puzzle, giving structure to the heart cells—which would just be a formless blob without it—but not exerting any active force on them.

“We don’t think previous methods of studying heart tissue capture the way the muscle would respond in your body,” says Chen, who’s also director of BU’s Biological Design Center and an associate faculty member at Harvard University’s Wyss Institute for Biologically Inspired Engineering. “This gives us the first opportunity to build something that mechanically is more similar to what we think the heart is actually experiencing—it’s a big step forward.”

To print each of the tiny components, the team used a process called two-photon direct laser writing—a more precise version of 3D printing. When light is beamed into a liquid resin, the areas it touches turn solid; because the light can be aimed with such accuracy—focused to a tiny spot—many of the components in the miniPUMP are measured in microns, smaller than a dust particle.

The decision to make the pump so small, rather than life-size or larger, was deliberate and is crucial to its functioning.

“The structural elements are so fine that things that would ordinarily be stiff are flexible,” says White. “By analogy, think about optical fiber: a glass window is very stiff, but you can wrap a glass optical fiber around your finger. Acrylic can be very stiff, but at the scale involved in the miniPUMP, the acrylic scaffold is able to be compressed by the beating cardiomyocytes.”

Chen says that the pump’s scale shows “that with finer printing architectures, you might be able to create more complex organizations of cells than we thought was possible before.” At the moment, when researchers try to create cells, he says, whether heart cells or liver cells, they’re all disorganized—“to get structure, you have to cross your fingers and hope the cells create something.” That means the tissue scaffolding pioneered in the miniPUMP has big potential implications beyond the heart, laying the foundation for other organs-on-a-chip, from kidneys to lungs.

Refining the Technology

According to White, the breakthrough is possible because of the range of experts on CELL-MET’s research team, which included not just mechanical, biomedical, and materials engineers like her, Chen, and Arvind Agarwal of Florida International University, but also geneticist Jonathan G. Seidman of Harvard Medical School and cardiovascular medicine specialist Christine E. Seidman of Harvard Medical School and Brigham and Women’s Hospital. It’s a breadth of experience that’s benefited not just the project, but Michas. An electrical and computer engineering student as an undergraduate, he says he’d “never seen cells in my life before starting this project.” Now, he’s preparing to start a new position with Seattle-based biotech Curi Bio, a company that combines stem cell technology, tissue biosystems, and artificial intelligence to power the development of drugs and therapeutics.

“Christos is someone who understands the biology,” says White, “can do the cell differentiation and tissue manipulation, but also understands nanotechnology and what’s required, in an engineering way, to fabricate the structure.”

The next immediate goal for the miniPUMP team? To refine the technology. They also plan to test ways to manufacture the device without compromising its reliability.

“There are so many research applications,” says Chen. “In addition to giving us access to human heart muscle for studying disease and pathology, this work paves the way to making heart patches that could ultimately be for someone who had a defect in their current heart.”

Other researchers on this project included Kamil Ekinci, a BU College of Engineering (ENG) professor of mechanical engineering and materials science and engineering, Jeroen Eyckmans, an ENG research assistant professor of biomedical engineering, M. Çağatay Karakan (ENG’22), and Pranjal Nautiyal, a postdoctoral researcher at the ​​University of Pennsylvania who recently completed his PhD at Florida International University.

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Gene Linked to Severe Learning Disabilities Governs Cell Stress Response

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DURHAM, N.C. – A gene that has been associated with severe learning disabilities in humans has been found to also play a vital role in cells’ response to environmental stress, according to a Duke University study appearing May 24 in the journal Cell Reports.

DURHAM, N.C. – A gene that has been associated with severe learning disabilities in humans has been found to also play a vital role in cells’ response to environmental stress, according to a Duke University study appearing May 24 in the journal Cell Reports.

Cells are stressed by factors  that may damage them, such as extreme temperatures, toxic substances, or mechanical shocks. When this happens, they undergo a range of molecular changes called the cellular stress response.

“Every cell, no matter from which organism, is always exposed to harmful substances in their environment that they have to deal with all the time,” said Gustavo Silva, assistant professor of biology at Duke and senior author on the paper. “Many human diseases are caused by cells not being able to cope with these aggressions.”

During the stress response, cells press pause the genes related to their normal housekeeping activities, and turn on genes related to crisis mode. Just like in a house being flooded, they put down the window cleaner, turn off the TV, and run to close the windows, then they patch holes, turn on the sump pump, and if needed, rip up carpet and throw away irreparably damaged furniture.

While studying mechanisms related to the cells’ health and their response to stress, the team saw that, under stress, a group of proteins was being modified inside the cells. They dug into it and found that the master regulator of this process is a gene called Rad6.

“When there is a stressor, cells need to change what proteins are produced,” said Vanessa Simões, associate in research in the Silva lab and lead author of the paper. “Rad6 goes in and gets the (protein-building) ribosomes to change their program and adapt what they are producing for the new stressful circumstances.”

Rad6 isn’t just any random gene. It can be found, sometimes under a different name, in almost all multicellular organisms. In humans, it is known for its association with a set of symptoms called “Nascimento Syndrome,” that include severe learning disabilities.

Nascimento Syndrome, also called X-linked intellectual disability type Nascimento, is still a poorly understood disease. It was officially described in 2006, and tends to run in families, giving scientists an early clue to its genetic causes. Affected individuals have severe learning disabilities, characteristic facial traits, with wide-set eyes and a depressed nose bridge, and a range of other debilitating symptoms.

Like many other genes, Rad6 doesn’t just do one thing. It’s a multiuse tool. By discovering an additional function, and one so tightly related to the cell’s health, Silva and his team get to add a new piece to the puzzle of Nascimento Syndrome.

“It’s still a big question or how exactly can a mutation to this gene lead to such a drastic syndrome in humans,” said Silva. “Our findings are exciting because Rad6 can be a model on which we can do genetic manipulations to try to understand how problems in coping with harmful conditions can be connected to how this disease progresses.”

“If we get a better understanding of how this gene works, we can actually try to interfere with it to help these patients have a better outcome.” he said.

But how does one actually “look” at what is happening with an infinitesimally small protein when a cell is stressed? With a fair amount of teamwork. Simões and Silva paired up with researchers from the Duke Biochemistry department and the Pratt School of engineering to gather all the help they needed.  

“We used biochemistry analyses, cellular assays, proteomics, molecular modeling, cryo-electron microscopy, a whole set of advanced techniques,” said Silva.

“It’s the cool thing about being in a place like Duke,” he said. “We found collaborators and resources easily, right here, and that really increases the impact of a study and our ability to do a more complete work.”

Funding for this study was provided by US National Institutes of Health R00 Award ES025835 and R35 Award GM137954 to Gustavo Silva. This work was also supported in part by R01 Award GM141223 to Alberto Bartesaghi and the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences Grant ZIC ES103326 to Mario J. Borgnia. Cryo- EM work was performed at the Duke University Shared Materials Instrumentation Facility (SMIF), a member of the North Carolina Research Triangle Nanotechnology Network (RTNN), which is supported by the National Science Foundation (grant ECCS- 1542015) as part of the National Nanotechnology Coordinated Infrastructure (NNCI). Funding was also provided from the UNC Lineberger Comprehensive Cancer Center through the University of California, Riverside Fund and the Cancer Center Support Grant P30CA016086. 

CITATION: “Redox-Sensitive E2 1 Rad6 Controls Cellular Response to Oxidative Stress Via K63-Linked Ubiquitination of Ribosomes,” Vanessa Simões, Blanche K. Cizubu, Lana Harley, Ye Zhou, Joshua Pajak, Nathan A Snyder, Jonathan Bouvette, Mario J. Borgnia, Gaurav Arya, Alberto Bartesaghi, and Gustavo M. Silva. Cell Reports, May 24 2022. DOI: 10.1016/j.celrep.2022.110860

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New Light-powered Catalysts Could Aid in Manufacturing

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CAMBRIDGE, MA — Chemical reactions that are driven by light offer a powerful tool for chemists who are designing new ways to manufacture pharmaceuticals and other useful compounds. Harnessing this light energy requires photoredox catalysts, which can absorb light and transfer the energy to a chemical reaction.

CAMBRIDGE, MA — Chemical reactions that are driven by light offer a powerful tool for chemists who are designing new ways to manufacture pharmaceuticals and other useful compounds. Harnessing this light energy requires photoredox catalysts, which can absorb light and transfer the energy to a chemical reaction.

MIT chemists have now designed a new type of photoredox catalyst that could make it easier to incorporate light-driven reactions into manufacturing processes. Unlike most existing photoredox catalysts, the new class of materials is insoluble, so it can be used over and over again. Such catalysts could be used to coat tubing and perform chemical transformations on reactants as they flow through the tube.

“Being able to recycle the catalyst is one of the biggest challenges to overcome in terms of being able to use photoredox catalysis in manufacturing. We hope that by being able to do flow chemistry with an immobilized catalyst, we can provide a new way to do photoredox catalysis on larger scales,” says Richard Liu, an MIT postdoc and the joint lead author of the new study.

The new catalysts, which can be tuned to perform many different types of reactions, could also be incorporated into other materials including textiles or particles.

Timothy Swager, the John D. MacArthur Professor of Chemistry at MIT, is the senior author of the paper, which appears today in Nature Communications. Sheng Guo, an MIT research scientist, and Shao-Xiong Lennon Luo, an MIT graduate student, are also authors of the paper.

Hybrid materials

Photoredox catalysts work by absorbing photons and then using that light energy to power a chemical reaction, analogous to how chlorophyll in plant cells absorbs energy from the sun and uses it to build sugar molecules.

Chemists have developed two main classes of photoredox catalysts, which are known as homogenous and heterogenous catalysts. Homogenous catalysts usually consist of organic dyes or light-absorbing metal complexes. These catalysts are easy to tune to perform a specific reaction, but the downside is that they dissolve in the solution where the reaction takes place. This means they can’t be easily removed and used again.

Heterogenous catalysts, on the other hand, are solid minerals or crystalline materials that form sheets or 3D structures. These materials do not dissolve, so they can be used more than once. However, these catalysts are more difficult to tune to achieve a desired reaction.

To combine the benefits of both of these types of catalysts, the researchers decided to embed the dyes that make up homogenous catalysts into a solid polymer. For this application, the researchers adapted a plastic-like polymer with tiny pores that they had previously developed for performing gas separations. In this study, the researchers demonstrated that they could incorporate about a dozen different homogenous catalysts into their new hybrid material, but they believe it could work more many more.

“These hybrid catalysts have the recyclability and durability of heterogeneous catalysts, but also the precise tunability of homogeneous catalysts,” Liu says. “You can incorporate the dye without losing its chemical activity, so, you can more or less pick from the tens of thousands of photoredox reactions that are already known and get an insoluble equivalent of the catalyst you need.”

The researchers found that incorporating the catalysts into polymers also helped them to become more efficient. One reason is that reactant molecules can be held in the polymer’s pores, ready to react. Additionally, light energy can easily travel along the polymer to find the waiting reactants.

“The new polymers bind molecules from solution and effectively preconcentrate them for reaction,” Swager says. “Also, the excited states can rapidly migrate throughout the polymer. The combined mobility of the excited state and partitioning of the reactants in the polymer make for faster and more efficient reactions than are possible in pure solution processes.”

Higher efficiency

The researchers also showed that they could tune the physical properties of the polymer backbone, including its thickness and porosity, based on what application they want to use the catalyst for.

As one example, they showed that they could make fluorinated polymers that would stick to fluorinated tubing, which is often used for continuous flow manufacturing. During this type of manufacturing, chemical reactants flow through a series of tubes while new ingredients are added, or other steps such as purification or separation are performed.

Currently, it is challenging to incorporate photoredox reactions into continuous flow processes because the catalysts are used up quickly, so they have to be continuously added to the solution. Incorporating the new MIT-designed catalysts into the tubing used for this kind of manufacturing could allow photoredox reactions to be performed during continuous flow. The tubing is clear, allowing light from an LED to reach the catalysts and activate them.

“The idea is to have the catalyst coating a tube, so you can flow your reaction through the tube while the catalyst stays put. In that way, you never get the catalyst ending up in the product, and you can also get a lot higher efficiency,” Liu says.

The catalysts could also be used to coat magnetic beads, making them easier to pull out of a solution once the reaction is finished, or to coat reaction vials or textiles. The researchers are now working on incorporating a wider variety of catalysts into their polymers, and on engineering the polymers to optimize them for different possible applications.

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The research was funded by the National Science Foundation and the KAUST Sensor Initiative.

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Watching Video Feed of Hospitalized Baby Improves Pumping Experience

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Parents who used videoconferencing technology to view their hospitalized baby reported an improved pumping experience while expressing milk for their premature infant. Videoconferencing also helped the whole family connect to their infant in the Neonatal Intensive Care Unit (NICU). These findings were published in Breastfeeding Medicinethis month.

Parents who used videoconferencing technology to view their hospitalized baby reported an improved pumping experience while expressing milk for their premature infant. Videoconferencing also helped the whole family connect to their infant in the Neonatal Intensive Care Unit (NICU). These findings were published in Breastfeeding Medicinethis month.

“Breast milk feeding is an essential component of care for the hospitalized premature infant, but it can be challenging due to factors including low milk supply, the need to express milk instead of feeding directly from the breast, as well as the stress and anxiety for new parents who are physically separated from their premature infants in the hospital environment,” said study lead author Adrienne Hoyt-Austin. “Our study explored the experience of pumping milk while watching one’s hospitalized baby with videoconferencing.”

The UC Davis Health study enrolled parents who used FamilyLink when they are not at the bedside in the UC Davis NICU. FamilyLink is a videoconferencing program which gives families the option to see their baby through a secure connection from a home computer, tablet or cellphone 24/7.

The team interviewed participants who pumped breastmilk while using FamilyLink to view their infant and those who pumped without videoconferencing.

Participants had given birth to an infant who was less than 34 weeks gestational age and was admitted to the UC Davis NICU.

In a one-on-one interview, participants were asked 14 open-ended questions regarding their breast milk pumping experience. The qualitative analysis identified four common themes. It showed that videoconferencing:

Provided bonding and connection. Participants felt “more of a connection” and “more of a bond” when seeing their hospitalized infant on video.
Provided motivation to pump. One participant said that seeing their baby is a “visual reminder that this is what I’m doing this for.”
Reminded participants that they were separated from their baby. One participant said, “I became just kind of guilty watching, feeling like I should be there instead of away.”
 Connected the whole family to their baby. Participants reported that videoconferencing helped introduce new family members to the baby and explain the complicated issue of neonatal hospitalization.

“In our interviews, we heard over and over again that that videoconferencing improved the pumping experience and gave motivation to continue to provide breast milk for their hospitalized infant. Participants also felt that seeing their baby while pumping strengthened the bond between the family with their newborn,” said Hoyt-Austin. “We hope that the use of videoconferencing for NICU parents will become a more widely available tool in NICUs that can help new parents in their breastfeeding journey.”       

The study co-authors are Iesha Miller, Kara Kuhn-Riordon, Jennifer Rosenthal, Caroline Chantry, James Marcin, Kristin Hoffman and Laura Kair, all of UC Davis Health.

The project was funded by the Children’s Miracle Network at UC Davis and the Clinical and Translational Science Center Highly-Innovative Award (UL1-TR001860). The researchers were supported by HRSA T32HP30037 grant, NIH’s Building Interdisciplinary Research Careers in Women’s Health (BIRCWH) award (K12 HD051958) and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) K23HD1015-50 grant.

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