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.”

Seismic wave data from the events could help researchers learn more about the interior layers of Mars, particularly its core-mantle boundary, researchers from InSight’s Marsquake Service (MQS) report in The Seismic Record.

Anna Horleston of the University of Bristol and colleagues were able to identify reflected PP and SS waves from the magnitude 4.2 event, called S0976a, and locate its origin in the Valles Marineris, a massive canyon network that is one of Mars’ most distinguishing geological features and one of the largest graben systems in the Solar System. Earlier orbital images of cross-cutting faults and landslides suggested the area would be seismically active, but the new event is the first confirmed seismic activity there.

S1000a, the magnitude 4.1 event recorded 24 days later, was characterized by reflected PP and SS waves as well as Pdiff waves, small amplitude waves that have traversed the core-mantle boundary. This is the first time Pdiff waves have been spotted by the InSight mission. The researchers could not definitively pinpoint S1000a’s location, but like S0976a it originated on Mars’ far side. The seismic energy from S1000a also holds the distinction of being the longest recorded on Mars, lasting 94 minutes.

Both marsquakes occurred in the core shadow zone, a region where P and S waves can’t travel directly to InSight’s seismometer because they are stopped or bent by the core. PP and SS waves don’t follow a direct path, but rather are reflected at least once at the surface before traveling to the seismometer.

“Recording events within the core shadow zone is a real steppingstone for our understanding of Mars. Prior to these two events the majority of the seismicity was within about 40 degrees distance of InSight,” said Savas Ceylan, a co-author from ETH Zürich. “Being within the core shadow, the energy traverses parts of Mars we have never been able to seismologically sample before.”

The two marsquakes differ in some important ways. S0976a is characterized by only low frequency energy, like many of the quakes identified so far on the planet, while S1000a has a very broad frequency spectrum. “[S1000a] is a clear outlier in our catalog and will be key to our further understanding of Martian seismology,” Horleston said.

S0976a is likely to have a much deeper origin than S1000a, she noted. “The latter event has a frequency spectrum much more like a family of events that we observe that have been modeled as shallow, crustal quakes, so this event may have occurred near the surface. S0976a looks like many of the events we have located to Cerberus Fossae — an area of extensive faulting — that have depths modeled to be around 50 kilometers or more and it is likely that this event has a similar, deep, source mechanism.”

Compared to the rest of the seismic activity detected by InSight, the two new far-side quakes are true outliers, the researchers said.

“Not only are they the largest and most distant events by a considerable margin, S1000a has a spectrum and duration unlike any other event previously observed. They truly are remarkable events in the Martian seismic catalog,” Horleston said.

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Researchers used a unique dataset to get a never-before-seen view of how science funding is spent and the results it produces.

The findings, published today (April 22, 2022) in the journal Science Advances, showed that funding of research by the National Institutes of Health mostly goes to hiring people who work on the projects funded by grants.

But these people — which includes staff and trainees like graduate students — go on to do more than just work on the grants for which they were hired, said Enrico Berkes, co-author of the study and postdoctoral researcher in economics at The Ohio State University.

“We see a great increase in productivity in publications directly linked to a grant but also in new studies that go beyond it,” Berkes said. “There is this ripple effect where people supported by the grant also produce other quality work.”

And the biomedical researchers who are the focus of this study produced more clinical research as the result of receiving more funding — studies directly related to patient care and health, said study co-author Bruce Weinberg, professor of economics at Ohio State.

“Funding is actually producing the kind of research that would lead to improvements in clinical outcomes for patients,” Weinberg said.

The key to this study is the UMETRICS dataset available through the Institute for Research on Innovation and Science. It provides detailed information concerning payments on sponsored research projects at 72 universities.

This allowed the researchers to use payments to identify all people working on research projects funded by NIH — from faculty members to trainees to staff.

Berkes, Weinberg and colleagues then used the PubMed database to find all research publications produced by the scientists in the UMETRICS database. They examined NIH grants between 1985 and 2020.

“We were able to link people to research projects by following the money,” Weinberg said. “This allowed us to answer a question that wasn’t possible before — how money spent on research impacts people.”

Results showed that 68% of grant funding went to spending on employees, which included faculty members, postdoctoral researchers, graduate and undergraduate students, research staff and other staff.

Increases in funding led labs to become more professionalized by hiring more staff and career researchers, findings showed. In fact, research and other staff showed a higher percentage of growth in employment than faculty members when funding increased.

As funding increased and research teams got larger, they produced more scientific papers — and the quality of research did not decline.

“One hypothesis would be that as teams grow larger, they would become more bureaucratic, and it would become more difficult to produce quality science. But we found that labs kept productivity up, likely because they become more professionalized,” Berkes said.

Findings showed that the largest increase in papers comes from studies not directly related to the grant. These are often papers that are not co-authored by the principal investigator, the researcher who is responsible for getting and managing the funding.

One way to understand the ripple effects of funding for medical research is to see how many research papers the people involved with the grants produce.

Unsurprisingly, faculty members have the largest increase in new scientific papers as the result of additional funding. But in relative terms, the trainees — including graduate students and postdoctoral researchers — have a larger-percentage increase in papers they produce.

“We can see how research funding is jump-starting the careers of trainees who take what they learn while working on these funded projects, and the collaborators they met on the grant, and start investigating other important issues,” Weinberg said.

Funding for biomedical research tends to increase both the number of clinical papers directly tied to patient care, and other types of medical research, results showed.

These findings may provide the best view yet of how federal grants awarded for research are spent, Berkes said.

“Funders tend to focus, understandably, on the impact of their money on the specific issue they funded,” Berkes said.

“But they should be aware of how their funding moves through a wide range of people and produces benefits they may have not expected.”

Funding for the study came from the National Institute on Aging, the Office of Behavioral and Social Science Research, the National Institute of General Medical Sciences, the National Center for Advancing Translational Sciences, the National Science Foundation, and the Ewing Marion Kauffman and Alfred P. Sloan foundations.

Other authors on the study were Reza Sattari, a former postdoctoral researcher, and Jung Bae, a PhD graduate, both from Ohio State.

The study, which was funded by Leronlimab maker CytoDyn Inc. and conducted by researchers either employed by or serving as consultants to the company, will be published online April 22 in the peer reviewed journal Clinical Infectious Diseases.

“While this was a small pilot study, it does suggest that some people with long COVID may actually have under-active immune systems after recovering from COVID-19, which means that boosting immunity in those individuals could be a treatment,” said senior author Dr. Otto Yang, a professor of medicine, division of infectious diseases, and of microbiology, immunology and molecular genetics at the David Geffen School of Medicine at UCLA.

COVID-19 is known to be caused by hyperactive immune responses against SARS-CoV-2 resulting in damage to lungs and other organs, and sometimes what is known as a “cytokine storm” that overwhelms the individual, which could lead to severe illness and death.

In a subset of persons who recover from the initial illness, various symptoms persist, such as fatigue, mental haziness, and shortness of breath, which can be debilitating and last for months. This is generally classified as long COVID, although symptoms vary widely and this syndrome is probably not a single disease entity. Limited understanding of its causes, however, makes finding ways to treat the condition particularly difficult.

Many scientists have suggested that persistence of immune hyperactivity after COVID-19 is a major contributor. Working under this theory, the researchers conducted a small exploratory trial of Leronlimab — an antibody that attaches to an immune receptor called CCR5 that is involved in inflammation — on 55 people with the syndrome.

Participants were randomly assigned to receive weekly injections of the antibody or a saline placebo for eight weeks, over which time they tracked any changes in 24 symptoms associated with long COVID, which also included loss of smell and taste, muscle and joint pain, and brain fog.

The researchers originally thought that blocking CCR5 with the antibody would dampen the activity of an overactive immune system after COVID-19 infection.

“But we found just the opposite,” Yang said. “Patients who improved were those who started with low CCR5 on their T cells, suggesting their immune system was less active than normal, and levels of CCR5 actually increased in people who improved. This leads to the new hypothesis that long COVID in some persons is related to the immune system being suppressed and not hyperactive, and that while blocking its activity, the antibody can stabilize CCR5 expression on the cell surface leading to upregulation of other immune receptors or functions.”

The findings, the researchers write, “suggests a complex role for CCR5 in balancing inflammatory and anti-inflammatory effects, e.g. through T regulatory cells,” although the results need to be confirmed in a larger, more definitive study.

Study co-authors are Norman Gaylis of Arthritis & Rheumatic Disease Specialties in Aventura, Florida; Angela Ritter of the Center for Advanced Research & Education in Gainesville, Georgia; Scott Kelly, Nader Pourhassan, and Christopher Recknor of CytoDyn Inc. in Vancouver, Washington; and Meenakshi Tiwary, Jonah Sacha, and Scott Hansen of Oregon Health & Science University.

Sacha, Hansen, and Yang are paid consultants for CytoDyn. Gaylis is on CytoDyn’s scientific board with stock options.

In a study published today they quantified regional fossil fuel CO₂ emissions reductions during the Covid-19 lockdowns of 2020-2021, using atmospheric measurements of CO₂ and oxygen (O₂) from the Weybourne Atmospheric Observatory, on the north Norfolk coast in the UK.

The estimate uses a new method for separating CO₂ signals from land plants and fossil fuels in the atmosphere. Previously it has not been possible to quantify changes in regional-scale fossil fuel CO₂ emissions with high accuracy and in near real-time.

Existing atmospheric-based methods have largely been unsuccessful at separating fossil fuel CO₂ from large natural CO₂ variability, so that estimates of changes, such as those occurring in response to the lockdowns, must rely on indirect data sources, which can take months or years to compile.

The atmospheric O₂-based method, published in the journal Science Advances, is in good agreement with three lower frequency UK emissions estimates produced during the pandemic by the Department for Business, Energy and Industrial Strategy, the Global Carbon Budget and Carbon Monitor, which used different methods and combinations of data, for example those based on energy usage.

Crucially, as well as being completely independent of the other estimates, this approach can be calculated much more quickly.

The researchers are also able to detect changes in emissions with higher frequency, such as daily estimates, and can clearly see two periods of reductions associated with two UK lockdown periods, separated by a period of emissions recovery when Covid restrictions were eased, during the summer of 2020.

Researchers at UEA — home of the UK’s only high-precision atmospheric O₂ measurement laboratory — worked with colleagues at Wageningen University in the Netherlands and the Max Planck Institute for Biogeochemistry, Germany.

The study’s lead author, Dr Penelope Pickers, of UEA’s Centre for Ocean and Atmospheric Sciences, said: “If humans are to reduce our CO₂ emissions from fossil fuels and our impact on the climate, we first need to know how much emissions are changing.

“Our study is a major achievement in atmospheric science. Several others, based solely on CO₂ data, have been unsuccessful, owing to large emissions from land plants, which obscure fossil fuel CO₂ signals in the atmosphere.

“Using atmospheric O₂ combined with CO₂ to isolate fossil fuel CO₂ in the atmosphere has enabled us to detect and quantify these important signals using a ‘top-down’ approach for the first time. Our findings indicate that a network of continuous measurement sites has strong potential for providing this evaluation of fossil fuel CO₂ at regional levels.”

Currently, fossil fuel CO₂ emissions are officially reported with a ‘bottom-up’ approach, using accounting methods that combine emission factors with energy statistics to calculate emissions.

These are then compiled into national inventories of estimated greenhouse gas (GHG) emissions to the atmosphere from anthropogenic sources and activities, such as domestic buildings, vehicles, and industrial processes.

However, inventories can be inaccurate, especially in less developed countries, which makes it more difficult to meet climate targets.

It can also take years for the inventory assessments to be completed, and at the regional scale, or on a monthly or weekly basis, the uncertainties are much larger.

An alternative method of estimating GHG emissions is to use a ‘top-down’ approach, based on atmospheric measurements and modelling.

The UK emissions inventory is already successfully informed and supported by independent top-down assessments for some key GHGs, such as methane and nitrous oxide.

But for CO₂, the most important GHG for climate change, this has never before been feasible, because of the difficulties distinguishing between CO₂ emissions from fossil fuels and land plant sources in the atmosphere.

Dr Pickers said: “The time taken for inventories to be completed makes it hard to characterise changes in emissions that happen suddenly, such as the reductions associated with the Covid pandemic lockdowns.

“We need reliable fossil fuel CO₂ emissions estimates quickly and at finer scales, so that we can monitor and inform climate change policies to prevent reaching 2°C of global warming.

“Our O₂-based approach is cost-effective and provides high frequency information, with the potential to provide fossil fuel CO₂ estimates quickly and at finer spatial scales, such as for counties, states or cities.”

The team used 10 years of high-precision, hourly measurements of atmospheric O₂ and CO₂ from Weybourne Atmospheric Observatory, which are supported by the UK’s National Centre for Atmospheric Science. Having long-term measurements of these climatically important gases was crucial to the success of the study.

To detect a Covid signal, they had to first remove the effects of atmospheric transport on their O₂ and CO₂ datasets, using a machine learning model.

They trained the machine learning model on pre-pandemic data, to estimate the fossil fuel CO₂ they would have expected to observe at Weybourne if the pandemic had never occurred.

They then compared this estimate to the fossil fuel CO₂ that was actually observed during 2020-2021, which revealed the relative reduction in CO₂ emissions.

‘Novel quantification of regional fossil fuel CO₂ reductions during COVID-19 lockdowns using atmospheric oxygen measurements’, Penelope A. Pickers et al., is published in Science Advances on Friday, April 22, 2022.