Heart cells cozy up to prevent deadly arrhythmias


Blood may seem like a simple fluid, but its chemistry is complex. When too much potassium, for instance, accumulates in the bloodstream, patients may experience deadly irregular heart rhythms.

Cardiovascular scientists at Virginia Tech’s Fralin Biomedical Research Institute at VTC are studying why.

In a new study, published in Pflügers Archiv European Journal of Physiology, the research team led by Steven Poelzing, associate professor at the institute, describes how subtle changes in potassium, calcium, and sodium levels regulate heartbeats.

Poelzing says that the results could help researchers and physicians understand the nuances of cardiac arrythmias, as well as a group of genetic disorders that impact sodium channel function, such as Brugada syndrome.

The scientists elevated blood potassium in guinea pigs, creating a condition called hyperkalemia, which causes some of the heart’s key electrical conduits, sodium channels, to shut down. Next, they increased calcium levels and observed the heart muscle cells pressing closer together. This miniscule motion—spanning mere nanometers—helps preserve electrical conduction in the heart.

“We know the heart is extremely sensitive to changes in blood electrolyte levels, but until recently we didn’t have a great picture of how the heart’s molecular landscape is remodeled, and how these muscle cells adapt,” said Poelzing, who is also an associate professor in the Virginia Tech College of Engineering’s department of biomedical engineering and mechanics.

Heart muscle cells primarily pass electrical signals via a network of protein bridges called gap junctions and sodium channels. These pathways let nutrients and positively charged minerals flow between cells. When there are too many positively charged potassium ions in the blood, however, the cells get overstimulated and temporarily block signaling channels.

“This can be dangerous when sodium channels get stuck in a half-closed state. The cell isn’t dying, but it’s not as electrically active as it once was. This can cause dangerous heart arrythmias and sudden cardiac death,” Poelzing said.

When the heart’s core electrical pathways falter, heart muscle cells press closer together, allowing them to sense subtle electric fields generated by neighboring cells. This secondary form of cell-to-cell signaling is known as ephaptic coupling.

“Ephaptic coupling appears to address the effects of a functional loss of sodium channels, in this case caused by high potassium, and helps keep the current flowing properly across the heart muscle,” Poelzing said.

Over the course of the eight-year study, Poelzing’s team tested different concentrations of sodium and calcium to treat the electrical defects associated with high potassium to see how the heart would respond. They discovered that increasing sodium and calcium levels together greatly reduced the distances between cells, providing a substantial improvement in cardiac conduction.

In the clinic, human patients with hyperkalemia who develop abnormal heart rhythms are administered intravenous calcium gluconate. Poelzing’s findings help explain why elevating calcium levels under these certain clinical conditions is beneficial.

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Researchers describe how embryonic stem cells keep optimal conditions for use in regenerative medicine

Researchers describe how embryonic stem cells keep optimal conditions for use in regenerative medicine

Scientists at the Proteomics Core Unit of the Spanish National Cancer Research Centre (CNIO), headed by Javier Muñoz, have described the mechanisms, unknown to date, involved in maintaining embryonic stem cells in the best possible state for their use in regenerative medicine. Their results, published in Nature Communications, will help to find novel stem-cell therapies for brain stroke, heart disease or neurodegenerative conditions like Alzheimer’s or Parkinson’s disease.

Naïve pluripotent stem cells, ideal for doing research

Embryonic stem cells (ESCs) are pluripotent cells that can grow into all somatic cell types—a characteristic that is extremely useful for researchers and regenerative medicine. There are two types of pluripotency: naïve and primed. The naïve state comes before the primed one during embryonic development. Naïve ESCs have the potential to differentiate into any cell types. Thus, they are more relevant in research. However, the naïve state is unstable, because naïve ESCs are constantly receiving signals that regulate the transition to the primed state and their self-renewal. Understanding the mechanisms that regulate the pluripotent states is important because they might help achieve long-term maintenance of stable naïve pluripotent stem cells in ESC cultures.

Traditionally, maintenance of naïve ESC cultures is based on the inhibition of two of the signaling pathways that regulate cell differentiation—aka as the 2i culture method. Recently, naïve ESCs have been maintained adopting a totally different approach, namely, the inhibition of Cdk8/19, a protein that regulates the expression of numerous genes, including the genes that help maintain the naïve state. “While the two approaches are used to culture naïve cells, little is known about the mechanisms involved,” says Javier Muñoz, who led the study.

Now, using proteomics, the large-scale characterisation of proteins coded in a genome, CNIO scientists have described a large number of the molecular events that help stabilize these valuable ESC. “This is the first time proteomics has been used in this context,” says Ana Martí­nez del Val, from the Proteomics Core Unit at CNIO, first author of the article. “We analyzed the mechanisms at a number of levels. First, we conducted phosphoproteomic analyses, studying phosphorylated proteins. Phosphorylation regulates protein functions (by activating or inhibiting them). Second, we analyzed the expression of these proteins. Finally, we identified changes in metabolites (reaction intermediates or end products). With our integrated approach, we got an accurate picture of the causes of the high degree of plasticity of ESC,” Martí­nez del Val explains.

The results of the study might have implications for research on some types of cancer. We know that “the inhibition of Cdk8 leads to reduced cell proliferation in acute myeloid leukemia by enhancing tumor suppressors”, and that “Cdk8 is a colorectal cancer oncogene.” “Cdk8 activity is somehow enigmatic, since its functions vary considerably with the cell environment,” says Muñoz. “We have identified a number of Cdk8 targets that were unknown until now. This can help understand the function this protein regulates in other biological contexts.”

Going beyond genomics with proteomics

The study by the CNIO team shows the need for a greater focus on proteomics in cancer research strategies.

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Cells burn more calories after just one bout of moderate aerobic exercise, study finds

Cells burn more calories after just one bout of moderate aerobic exercise, OSU study finds

In a recent study testing the effects of exercise on overall metabolism, researchers at Oregon State University found that even a single session of moderate aerobic exercise makes a difference in the cells of otherwise sedentary people.

Mitochondria are the part of the cell responsible for the biological process of respiration, which turns fuels such as sugars and fats into energy, so the researchers focused only on mitochondria function.

“What we found is that, regardless of what fuel the mitochondria were using, there were mild increases in the ability to burn off the fuels,” said Matt Robinson, lead author on the study and an assistant professor in the College of Public Health and Human Sciences.

OSU researchers recruited participants who do not follow a regular exercise routine and had them ride a stationary bike for an hour at a moderate intensity. They biopsied their muscles 15 minutes later to test how efficient the mitochondria were after the exercise was completed and compared those results with a resting day.

Post-exercise, study participants’ mitochondria burned 12-13% more fat-based fuel and 14-17% more sugar-based fuel. While the effects were not drastic, they were consistent, Robinson said.

“It’s pretty remarkable that even after just one hour of exercise, these people were able to burn off a little more fuel,” he said.

Previous research in the field has long established that regular exercise creates lasting change in people’s metabolism, making their bodies burn more energy even when they’re not working out.

Prior studies have looked at highly trained or athletic people, but Robinson’s team wanted to look specifically at singular bouts of exercise in people who were generally active and disease-free but who did not have structured exercise regimes. These people were on the lower end of fitness, which is associated with low mitochondrial abundance and energy production. Participants were monitored while working out at approximately 65% of their maximal effort, where they could keep up the cycling pace for an hour or more and still comfortably carry on a conversation.

Robinson said they’re hoping these results help break down the mental barrier of people thinking they need to be elite athletes for exercise to make an impact on their health.

“From a big picture health perspective, it’s very encouraging for people to realize that you can get health benefits from a single session of exercise,” Robinson said. “We’re trying to encourage people, ‘You did one, why don’t you try to do two? Let’s do three.’

“We know that exercise is good for you, in general. But those benefits of that single bout of exercise seem to fade away after a day or two. You get the long-term benefits when you do that exercise again and again and you make it a regular habit.”

In this study, Robinson’s research team focused narrowly on mitochondria to find out how big a role mitochondria play in the overall function of muscle metabolism. Other studies are looking at changes in blood flow to the muscle and how the muscle metabolizes fats versus sugars.

From a disease perspective, Robinson said it’s clear that obesity and diabetes involve impairments in metabolism. Physiologically, when the body undergoes exercise, sugars tend to be burned off first while fats are stored, but in cases of diabetes and obesity, there is some dysregulation in metabolism that causes the body to not be able to switch between the two types of fuel.

Exercise can help reset that system, he said.

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Scientists identify cells responsible for liver tissue maintenance and regeneration

Scientists identify cells responsible for liver tissue maintenance and regeneration

While the amazing regenerative power of the liver has been known since ancient times, the cells responsible for maintaining and replenishing the liver have remained a mystery. Now, research from the Children’s Medical Center Research Institute at UT Southwestern (CRI) has identified the cells responsible for liver maintenance and regeneration while also pinpointing where they reside in the liver.

These findings, reported today in Science, could help scientists answer important questions about liver maintenance, liver damage (such as from fatty liver or alcoholic liver disease), and liver cancer.

The liver performs vital functions, including chemical detoxification, blood protein production, bile excretion, and regulation of energy metabolism. Structurally, the liver is comprised of tissue units called lobules that, when cross-sectioned, resemble honeycombs. Individual lobules are organized in concentric zones in which hepatocytes, the primary liver cell type, carry out diverse functions. Over the past 10 years, there has been debate about whether all hepatocytes across the lobule contribute to the production of new cells or if a certain subset of hepatocytes or stem cells is responsible.

Previous efforts to identify the cells most responsible for liver regeneration were hindered by a lack of markers to distinguish and compare the functions of distinct types of hepatocytes in different regions of the liver. Scientists in the Zhu lab addressed this issue by comparing the genes that mark hepatocytes throughout the liver. Using this approach, they identified genes that were only turned on by specific subsets of hepatocytes, and then used these genes as markers to distinguish the identities and functions of different hepatocyte subsets. They created 11 new mouse strains, each of which carries a marker for a specific subset of hepatocytes. Along with three previously established mouse strains, researchers observed how the labeled cells multiplied or disappeared over time, and which were responsible for liver regeneration after damage. These experiments allowed researchers to directly compare how different subsets of hepatocytes contributed to liver maintenance and regeneration.

Members of the Zhu lab discovered that cells in zone 2 gave rise to new hepatocytes that populated all three zones of liver lobules while cells from zones 1 and 3 disappeared. These unexpected observations suggested that there is not a rare population of stem cells responsible for liver maintenance, but instead, a common set of mature hepatocytes within a specific region of the liver that regularly divide to make new hepatocytes throughout the liver. The Zhu lab also exposed mice to chemicals that mimicked common forms of liver damage, showing that cells in zone 2 were most able to evade death, regenerate hepatocytes, and sustain liver function.

“In humans, cells in zones 1 and 3 are most often harmed by alcohol, acetaminophen, and viral hepatitis. So it makes sense that cells in zone 2, which are sheltered from toxic injuries affecting either end of the lobule, would be in a prime position to regenerate the liver. However, more investigation is needed to understand the different cell types in the human liver,” says Hao Zhu, M.D., an associate professor at CRI and lead author of the study.

To learn more about mechanisms that hepatocytes in zone 2 use to regenerate liver function, members of the Zhu lab performed genetic screens to look for genes important for growth and regeneration. They discovered a pathway known as the IGFBP2-mTOR-CCND1 axis that was active in zone 2 but less so in zones 1 and 3. When they deleted components of this pathway from mice, the cells in zone 2 no longer gave rise to new hepatocytes, establishing that this was the mechanism responsible for the regenerative capacity of zone 2 cells.

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How coronavirus damages lung cells within mere hours

How coronavirus damages lung cells within mere hours

What if scientists knew exactly what impact the SARS-CoV-2 virus had inside our lung cells, within the first few hours of being infected? Could they use that information to find drugs that would disrupt the virus’ replication process before it ever gets fully underway? The discovery that several existing FDA-approved drugs—including some originally designed to fight cancer—can stop coronavirus in its tracks indicates the answer is a resounding yes.

A team of Boston University researchers—hailing from BU’s National Emerging Infectious Diseases Laboratories (NEIDL), the Center for Regenerative Medicine (CReM) at BU’s Medical Campus, and BU’s Center for Network Systems Biology (CNSB)—embarked on a months-long, collaborative and interdisciplinary quest, combining multiple areas of expertise in virology, stem cell-derived lung tissue engineering, and deep molecular sequencing to begin answering those questions. They simultaneously infected tens of thousands of human lung cells with the SARS-CoV-2 virus, and then tracked precisely what happens in all of those cells during the first few moments after infection. As if that was not complicated enough, the team had to cool their entire high-containment research facility inside the NEIDL to a brisk 61 degrees Fahrenheit.

The result of that challenging and massive undertaking? The BU team has revealed the most comprehensive map to date of all the molecular activities that are triggered inside lung cells at the onset of coronavirus infection. They also discovered there are at least 18 existing, FDA-approved drugs that could potentially be repurposed to combat COVID-19 infections shortly after a person becomes infected. Experimentally, five of those drugs reduced coronavirus spread in human lung cells by more than 90 percent. Their findings were recently published in Molecular Cell.

Now, academic and industry collaborators from around the world are in contact with the team about next steps to move their findings from bench to bedside, the researchers say. (Although COVID-19 vaccines are starting to be rolled out, it’s expected to take the better part of a year for enough people to be vaccinated to create herd immunity. And there are no guarantees that the current vaccine formulations will be as effective against future SARS-CoV-2 strains that could emerge over time.) More effective and well-timed therapeutic interventions could help reduce the overall number of deaths related to COVID-19 infections.

“What makes this research unusual is that we looked at very early time points [of infection], at just one hour after the virus infects lung cells. It was scary to see that the virus already starts to damage the cells so early during infection,” says Elke Mühlberger, one of the study’s senior investigators and a virologist at BU’s NEIDL. She typically works with some of the world’s most lethal viruses like Ebola and Marburg.

“The most striking aspect is how many molecular pathways are impacted by the virus,” says Andrew Emili, another of the study’s senior investigators, and the director of BU’s CNSB, which specializes in proteomics and deep sequencing of molecular interactions. “The virus does wholesale remodeling of the lung cells—it’s amazing the degree to which the virus commandeers the cells it infects.”

Viruses can’t replicate themselves because they lack the molecular machinery for manufacturing proteins—that’s why they rely on infecting cells to hijack the cells’ internal machinery and use it to spread their own genetic material. When SARS-CoV-2 takes over, it completely changes the cells’ metabolic processes, Emili says, and even damages the cells’ nuclear membranes within three to six hours after infection, which the team found surprising. In contrast, “cells infected with the deadly Ebola virus don’t show any obvious structural changes at these early time points of infection, and even at late stages of infection, the nuclear membrane is still intact,” Mühlberger says.

The nuclear membrane surrounds the nucleus, which holds the majority of a cell’s genetic information and controls and regulates normal cellular functions. With the cell nucleus compromised by SARS-CoV-2, things rapidly take a bad turn for the entire cell. Under siege, the cells—which normally play a role in maintaining the essential gas exchange of oxygen and carbon dioxide that occurs when we breathe—die. As the cells die, they also emit distress signals that boost inflammation, triggering a cascade of biological activity that speeds up cell death and can eventually lead to pneumonia, acute respiratory distress, and lung failure.

“I couldn’t have predicted a lot of these pathways, most of them were news to me,” says Andrew Wilson, one of the study’s senior authors, a CReM scientist, and a pulmonologist at Boston Medical Center (BMC), BU’s teaching hospital. At BMC, Boston’s safety net hospital, Wilson has been on the front lines of the COVID-19 pandemic since March 2020, trying to treat and save the sickest patients in the hospital’s ICU. “That’s why our [experimental] model is so valuable.”

The team leveraged the CReM’s organoid expertise to grow human lung air sac cells, the type of cell that lines the inside of lungs. Air sac cells are usually difficult to grow and maintain in traditional culture and difficult to extract directly from patients for research purposes. That’s why much coronavirus research to date by other labs has relied on the use of more readily available cell types, like kidney cells from monkeys. The problem with that is kidney cells from monkeys don’t react the same way to coronavirus infection as lung cells from humans do, making them a poor model for studying the virus—whatever is learned from them doesn’t easily translate into clinically relevant findings for treating human patients.

“Our organoids, developed by our CReM faculty, are engineered from stem cells—they’re not identical to the living, breathing cells inside our bodies, but they are the closest thing to it,” says Darrell Kotton, one of the study’s senior authors. He is a director of the CReM and a pulmonologist at BMC, where he has worked alongside Wilson in the ICU treating COVID-19 patients. The two of them often collaborated with Mühlberger, Emili, and other members of their research team via Zoom calls that they managed to join during brief moments of calm in the ICU.

In another recent study using the CReM’s engineered human lung cells, the research team confirmed that existing drugs remdesivir and camostat are effective in combating the virus, though neither is a perfect fix for controlling the inflammation that COVID-19 causes. Remdesivir, a broad-use antiviral, has already been used clinically in coronavirus patients. But based on the new study’s findings that the virus does serious damage to cells within hours, setting off inflammation, the researchers say there’s likely not much that antiviral drugs like remdesivir can do once an infection has advanced to the point where someone would need to be put on a ventilator in the ICU. “[Giving remdesivir] can’t save lives if the disease has already progressed,” Emili says.

Seeing how masterfully SARS-CoV-2 commandeers human cells and subverts them to do the manufacturing work of replicating the viral genome, it reminded the researchers of another deadly invader.

“I was surprised that there are so many similarities between cancer cells and SARS-CoV-2-infected cells,” Mühlberger says. The team screened a number of cancer drugs as part of their study and found that several of them are able to block SARS-CoV-2 from multiplying. Like viruses, cancer cells want to replicate their own genomes, dividing over and over again. To do that, they need to produce a lot of pyrimidine, a basic building block for genetic material. Interrupting the production of pyrimidine—using a cancer drug designed for that purpose—also blocks the SARS-CoV-2 genome from being built. But Mühlberger cautions that cancer drugs typically have a lot of side effects. “Do we really want to use that heavy stuff against a virus?” she says. More studies will be needed to weigh the pros and cons of such an approach.

The findings of their latest study took the four senior investigators and scientists, postdoctoral fellows, and graduate students from their laboratories almost four months, working nearly around the clock, to complete the research. Of critical importance to the team’s leaders was making sure that the experimental setup had rock-solid foundations in mimicking what’s actually happening when the SARS-CoV-2 virus infects people.

“Science is the answer—if we use science to ask the lung cells what goes wrong when they are infected with coronavirus, the cells will tell us,” Kotton says. “Objective scientific data gives us hints at what to do and has lessons to teach us. It can reveal a path out of this pandemic.”

He’s particularly excited about the outreach the team has received from collaborators around the world. “People with expertise in supercomputers and machine learning are excited about using those tools and the datasets from our publication to identify the most promising drug targets [for treating COVID-19],” he says.

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Parkinson’s disease risk and severity is tied to a channel in cells’ ‘recycling centers

Parkinson's disease

Many genetic mutations have been found to be associated with a person’s risk of developing Parkinson’s disease. Yet for most of these variants, the mechanism through which they act remains unclear.

Now a new study in Nature led by a team from the University of Pennsylvania has revealed how two different variations—one that increases disease risk and leads to more severe disease in people who develop Parkinson’s and another that reduces risk—manifest in the body.

The work, led by Dejian Ren, a professor in the School of Arts & Sciences’ Department of Biology, showed that the variation that raises disease risk, which about 17% of people possess, causes a reduction in function of an ion channel in cellular organelles called lysosomes, also known as cells’ waste removal and recycling centers. Meanwhile, a different variation that reduces Parkinson’s disease risk by about 20% and is present in 7% of the general population enhances the activity of the same ion channel.

“We started with the basic biology, wanting to understand how these lysosomal channels are controlled,” says Ren. “But here we found this clear connection with Parkinson’s disease. To see that you can have a variation in an ion channel gene that can change the odds of developing Parkinson’s both ways—increasing and decreasing it—is highly novel.”

The fact that the channel seems to play a crucial role in Parkinson’s also makes it an appealing potential target for a drug that could slow the disease’s progression, the researchers note.

Scientists have understood since the 1930s that cells use carefully regulated ion channels embedded in their plasma membrane to control crucial aspects of their physiology, such as shuttling electrical impulses between neurons and from neurons to muscles.

But it wasn’t until the past decade that researchers began to appreciate that the organelles within cells that have membranes, including endosomes and lysosome, also relied on ion channels to communicate.

“One reason is it’s hard to look at them because organelles are really small,” Ren says. During the last several years, his lab overcame this technical challenge and began studying these membrane channels and measuring the current of ions that crosses through them.

These ions pass through channel proteins that open and close in response to specific factors. About five years ago, Ren’s group identified one membrane protein, TMEM175, that forms a channel allowing potassium ions to move in and out.

Around the same time, other teams doing genome-wide association studies found two variations in TMEM175 that influenced Parkinson’s disease risk, turning it up or down.

“One variation is associated with a 20-25% increase in the odds of getting Parkinson’s in the general population,” Ren says. “And if you look only at people who have been diagnosed with Parkinson’s, the frequency of that variation is even higher.”

Intrigued by the connection, Ren reached out to Penn physician-scientist Alice Chen-Plotkin, who works with patients who have Parkinson’s, to collaborate. In data from Parkinson’s disease patients, she and colleagues found that motor and cognitive impairments progressed more rapidly in those patients who carried one of the TMEM175 genetic variations Ren was studying.

To find out what this variation was actually doing in cells, Ren’s lab turned a close eye to lysosomes. In isolation, they found that the potassium current through TMEM175 was activated by growth factors, proteins like insulin that respond to the presence of nutrients in the body. And they confirmed that TMEM175 appeared to be the only active potassium channel in mouse lysosomes.

“When you starve a cell, this protein is not functional anymore,” Ren says. “That was exciting to us because that tells us this is a major mechanism that can be used by the organelle to receive communications from the outside of the cell and maybe send communication back out.”

They found that a kinase enzyme called AKT, which is typically thought to achieve its ends by adding a small molecule called a phosphate group to whatever protein it is acting upon, joined with TMEM175 to open the protein channel. But AKT opened it without introducing a phosphate group. “The textbook definitation of a kinase is that it phosphorylates proteins,” Ren says. “To find this kinase acting without doing that was very surprising.”

They next turned to mice genetically engineered to carry the same variations that had been found in the human population to see how the genetic changes affected the animals’ ion channel activity. Mice with the disease-risk-increasing mutation had a potassium current of just about 50% of that of normal mice, and that current was extinguished in the absence of growth factors. In contrast, the ion channels in mice with the disease-risk-reducing mutation continued operating for several hours in the absence of growth factors, even longer than they did in normal mice.

“This tells you this mutation is somehow helping the mice resist the effects of nutrient depletion,” Ren says.

To measure effects on neurons, they observed that the neurons with the mutation in cell culture associated with more severe Parkinson’s were more susceptible to damage from toxins and nutrient depletion. “If the same is true in human neurons, that means 17% of the population carries a variation that may make their neurons more damaged when subjected to stressors,” says Ren.

Collaborating with Penn researcher Kelvin Luk, the investigators looked at levels of misfolded protein in neurons in cell culture. Known in humans as Lewy bodies and a defining characteristic of Parkinson’s, these inclusions increased “strikingly” within neurons when TMEM175 function declined, Ren says. This is likely due to an impairment in the function of lysosomes, which normally help digeset and recycle waste generated by the cell.

And, also associated with human Parkinson’s, mice lacking TMEM175 lost a portion of the neurons that produce the neurotransmitter dopamine and performed worse on tests of coordination than normal mice.

Together with the findings in humans, the researchers believe their work points to a significant contributor to the pathology of Parkinson’s disease. Moving forward, Ren’s group hopes to delve deeper into the mechanism through which this ion channel is regulated. Their research may shed light not only on the molecular impairments involved in Parkinson’s but also in other neurodegenerative diseases, particular those related to lysosomes, which include a number of rare but very severe conditions.

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Study on placenta membrane cells identifies genetic markers associated with preterm birth

A new research study from the March of Dimes Prematurity Research Center led by investigators at the University of Chicago has identified new genetic markers associated with gestational length, providing new insights into potential risk factors for preterm birth.

In a collaboration between multiple labs and funded through the March of Dimes Foundation, the investigators set out to map important gene regulatory regions and genetic markers relevant to preterm birth. Their first challenge was addressing the lack of functional genomics data in pregnancy-relevant tissue types.

“When you’re studying a disease, there are typically a lot of genetic and tissue resources available in public databases,” said co-senior author Carole Ober, Ph.D., Chair of Human Genetics at UChicago. “But pregnancy related conditions, like preterm birth, get much less attention or funding, and as a result pregnancy-relevant tissues are not well represented in those databases.”

The paper, published on Dec. 2, 2020 in Science Advances, focused on decidualized cells derived from the endometrial cells attached to the placenta. Decidualized cells line the uterus during the latter half of the menstrual cycle, preparing it for implantation and supporting the growth and development of the placenta and fetus throughout pregnancy.

The investigators collected placental tissue donated by patients who had given birth and isolated the decidualized cells in the lab. Genetic analysis of these cells identified two new candidate preterm birth genes, HAND2 and GATA2.

“These genes are both important transcription factors that regulate the expression of several other genes,” said co-first author Ivy Aneas, Ph.D., a research associate professor of human genetics at UChicago. “HAND2 mediates the effect of progesterone on the uterine epithelium while GATA2 is involved in stem cell maintenance.”

Both of these processes and the genes that control them are known to be important for endometrial decidualization and embryo implantation.

“The fact that we identified a link between these two genes and the duration of gestation suggests that their roles in pregnancy may be more important than previously anticipated,” said co-first author Noboru Sakabe, Ph.D., a staff scientist at UChicago.

Understanding how these genes contribute to the length of pregnancy could be a key to developing new preventions against preterm birth.

“Researchers have recognized a number of factors that can lead to preterm birth, ranging from environmental to infectious disease and beyond, but what is vexing is that we haven’t been successful in preventing it,” said co-senior author Marcelo Nobrega, MD, Ph.D., professor of human genetics at UChicago. “Our research took a look at the genetics and allowed us to pull out some links that might illuminate genetic pathways and signaling molecules involved in the decidualization process, which in turn might provide new targets for therapies.”

The researchers were able to leverage combined expertise in human genetics, genomics and statistical analysis to combine data gathered from human endometrial cells in the lab with data from existing genome-wide association studies (GWAS) to zero in on key genetic variations that may be linked to preterm birth.

“Only six or seven genomic regions have been linked to preterm birth and gestational length,” said co-senior author Xin He, Ph.D., assistant professor of human genetics at UChicago. “We don’t know which genes are involved or how that influences cell function and risk of preterm birth. With our approach, we integrated genomics data generated from our center and integrated it with other databases to identify the underlying genetic interactions. This can lead us to genes that may be involved in this condition, which gives us a hint to the underlying biology.”

While genetic factors are thought to play only a small role in the risk of preterm birth, the investigators were glad to see such clear results in their study.

“Preterm birth is so common, and some people experience it repeatedly,” said Ober. “If you have a preterm birth, it doesn’t matter if it’s genetic or not, you just don’t want to experience one again. We can now use this information to better understand some of the genetic component and how it plays a role in the condition.”

Future research will investigate other kinds of cells that may play key roles in pregnancy and preterm birth, such as the immune cells that reside at the maternal-fetal interface, and grow the “roadmap” of genomic variations in endometrial cells by examining the effects of varied environmental conditions on gene expression.

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Scientists identify compound that stimulates muscle cells in mice

UCLA researchers have identified a compound that can reproduce the effect of exercise in muscle cells in mice. The findings are published in the journal Cell Reports Medicine.

Normally, muscles get stronger as they are used, thanks to a series of chemical signals inside muscle cells. The newly identified compound activates those signals, which suggests that compounds like it could eventually be used to treat people with limb girdle muscular dystrophy, a form of adolescent-onset muscular dystrophy.

When muscles aren’t worked regularly, they gradually atrophy. (The phenomenon is familiar to anyone who’s had a cast on their leg for several weeks.) Fortunately, for people with healthy muscles, that deterioration is reversible. Muscle use stimulates chemical messengers inside the muscle cells that increase muscle mass and strength.

People with the muscle wasting disease limb girdle muscular dystrophy have a genetic defect that interferes with that chemical messenger, making their muscles unable to respond to exercise. No amount of exercise can trigger the signal to strengthen their muscles. Because the muscles never get the message, they gradually wither, and people with the disease end up in wheelchairs, almost completely paralyzed.

“It’s really dramatic. When these patients lose muscle, they struggle to gain it back,” said Melissa Spencer, the paper’s senior author and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA.

The genetic defect responsible for limb girdle muscular dystrophy causes shortages of an enzyme in muscle cells called CaMK. CaMK is responsible for launching a chain of chemical signals that turns on genes to boost the cell’s ability to grow and metabolize fat, which is used as an energy source.

“CaMK activates genes that promote muscle growth and fat metabolism,” said Spencer, who is also a professor of neurology and the director of the neuromuscular program at the David Geffen School of Medicine at UCLA.

To find a drug that could help restore the signals related to CaMK, Spencer and her colleagues worked with Robert Damoiseaux, director of UCLA’s Molecular Shared Screening Resource, to screen more than 2,000 compounds to see which ones worked in lab-grown muscle cells. So far, they have tested 14 promising candidates in mice who had a genetic defect comparable to the one that causes limb girdle muscular dystrophy in people.

The testing identified a chemical compound called AMBMP that allowed mouse muscles to work and grow the way healthy muscle cells do.

“When we put the drug into mice, we found that it activated CaMK and restored all the properties we had observed as defective in our disease model,” Spencer said.

Spencer and her collaborators are planning further studies to understand how AMBMP affects CaMK and to identify similar compounds that could be more effective in humans.

UCLA neurology professor Vargehese John, associate researcher Irina Kramerova and staff research associate Jesus Campagna, co-authors of the new study, are already producing new compounds similar to AMBMP. Spencer and Kramerova will test those compounds in mice to determine the best drug candidate to advance to clinical trials.

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Drug tricks cancer cells by impersonating a virus

A new cancer drug helps the immune system destroy tumors by impersonating a virus and “infecting” cancer cells.

The drug, called BO-112, is in human trials and mimics the structure of a double-stranded RNA molecule, a type of genetic material found in some viruses. Viruses inject their RNA into cells during infection, but cells can spot this viral RNA using specific receptors, and call upon the immune system to intervene when viruses strike.

BO-112 takes advantage of this cellular defense mechanism — once injected inside a tumor, the drug helps to alert the body’s immune system to the cancer’s presence. To hide from the immune system, cancer cells often cloak themselves in disguises, and also stop signals that could alert the body of their location. But when treated with BO-112, tumors throw up red flags that the immune system can spot.

The drug, which has been tested in mice and a a few dozen people, could help amplify the effects of existing cancer treatments designed to rally the immune system, study author Dr. Anusha Kalbasi, an assistant professor of radiation oncology at the University of California, Los Angeles and member of the UCLA Jonsson Cancer Center, told Live Science in an email. 

In other words, once BO-112 reveals the location of a tumor, other treatments could more easily target it. “I do think the power of BO-112 is in its ability to enable other immunotherapies to maximize their benefit,” Kalbasi said. 

In a new study, published Oct. 14 in the journal Science Translational Medicine, Kalbasi and his colleagues tested BO-112 in lab dish experiments and a mouse model of melanoma, a kind of skin cancer. In a separate clinical trial, published the same day, 44 human patients took BO-112 with and without additional cancer treatments, so researchers could begin to analyze how safe and effective the drug is in people. The early results hint that BO-112 can make tough-to-treat tumors vulnerable to immunotherapy, but the team now needs to confirm that those results hold up in larger groups. 

Unmasking cancer cells 

Cancer immunotherapy works by ramping up the body’s immune defense against tumors, but cancer cells use various tricks to resist these attacks. 

For instance, an immunotherapy called “adoptive T cell therapy” involves extracting a patient’s immune cells, modifying them to better recognize specific tumors and then reintroducing them to the body, according to a statement. These T cells detect tumors by scanning for specific molecules on their surfaces, called antigens — but some tumors can slow or stop production of these antigens, or prevent them from being displayed on a cell’s surface, thanks to specific genetic mutations, making them effectively invisible to T cells.

In theory, forcing such tumors to build and present antigens on their surface would make them visible to T cells; Kalbasi and his colleagues tested this idea in several mouse studies.

They first engineered mouse tumor cells with mutations that would reduce the number of antigens on their surfaces. In lab dish studies, the mutant tumor cells could not be detected by T cells.   

But when the team turned on a gene called NLRC5 in the engineered tumors, the cells generated antigens in spite of the other mutations they’d introduced. Activating this gene made the tumor cells visible to T cells, leaving the cancer open to attack. The same strategy worked when the team moved from lab dishes to actual lab mice; however, for the same approach to work in humans, scientists would need to somehow turn on the NLRC5 gene in a patient’s tumor cells. 

To achieve the same result more practically, the team turned to BO-112. Similar to NLRC5, the drug makes cancer cells produce antigens; rather than switching on a specific gene, the drug instead tricks the tumor into reacting as if it’s being infected by a virus.

Without an injection of BO-112, the lab mice’s tumors did not succumb to adoptive T cell therapy, because the T cells could not detect the tumors in the first place. However, after the injection, the T cell treatment suddenly worked, Kalbasi said.

“When we added BO-112, the tumors either decreased in size or stopped growing for a period of time,” he said.

From mice to humans

However, in mice with large tumors, the cancer eventually began to grow again, Kalbasi noted. In mice with small tumors, the combinatory treatment was more effective, as the tumors shrunk more dramatically in size and sometimes disappeared altogether, he said.

To probe whether B0-112 works in human patients as it does in mice, another group of researchers conducted a small clinical trial, sponsored by the pharmaceutical company Highlight Therapeutics. Most of the patients handled the treatment well, although three of the 44 participants experienced a severe reaction, including lung inflammation and a significant drop in platelet levels, which are important for blood clotting, according to the report. 

Of the 44 patients, 28 patients who did not experience these side effects received injections of B0-112 along with existing immunotherapy drugs, called nivolumab and pembrolizumab. These treatments “remove the brakes off the body’s T cells” so they can target tumors more effectively, Kalbasi said. In the clinical trial, BO-112 made tumors more sensitive to these two drugs; after eight to 12 weeks of treatment, 10 patients with metastatic cancer reached “stable disease,” meaning their tumors had stopped growing, while the tumors of three other patients actually began to shrink. 

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That said, “the number of patients is too low to draw a formal conclusion about the responses because the main objective of this first in-human clinical trial was safety,” the authors wrote. However, these early results hint that BO-112 could be an effective strategy to take down tumors that are resistant to immunotherapy, they noted.

“Every cell type has a different capacity to sense double-stranded RNA,” the molecule that BO-112 mimics, Kalbasi added. “So we will be watching carefully to learn what factors in each patient may predict a better response to BO-112,” since some cancers might be more sensitive to the treatment than others. Given that BO-112 is currently administered as a direct injection into tumors, initial trials will likely focus on cancer types with “superficially accessible” tumors, such as melanoma, lymphoma, breast cancer and bladder cancer, said Dr. Joshua Brody, director of the Lymphoma Immunotherapy Program at the Icahn School of Medicine at Mount Sinai, who was not involved in the study.

“The exciting opportunity presented by these two studies, both in the lab and in patients, is that we have medicines that can improve antigen presentation and thereby make immunotherapies — which would otherwise fail — become effective in inducing cancer remissions,” Brody told Live Science in an email.

Originally published on Live Science. 

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Study identifies brain cells most affected by epilepsy and new targets for their treatment

Epilepsy is one of the most common neurological diseases. It is caused by a malfunction in brain cells and is usually treated with medicines that control or counteract the seizures.

Scientists from the Faculty of Health and Medical Sciences, University of Copenhagen and Rigshospitalet have now identified the exact neurons that are most affected by epilepsy. Some of which have never been linked to epilepsy before. The newfound neurons might contribute to epileptogenesis—the process by which a normal brain develops epilepsy—and could therefore be ideal treatment targets.

“Our findings potentially allows for the development of entirely new therapeutic approaches tailored towards specific neurons, which are malfunctioning in cases of epilepsy. This could be a breakthrough in personalized medicine-based treatment of patients suffering from epileptic seizures,” says Associate Professor Konstantin Khodosevich from Biotech Research & Innovation Center (BRIC), Faculty of Health and Medical Sciences.

A major step towards more effective drugs

It is the first time a study investigates how every single neuron in the epileptic zone of the human brain is affected by epilepsy. The researchers have analyzed more than 117,000 neurons, which makes it the largest single cell dataset for a brain disorder published so far.

Neurons have been isolated from tissue resected from patients being operated as part of the Danish Epilepsy Surgery Programme at Rigshospitalet in Copenhagen.

“These patients continue to have seizures despite the best possible combination of anti-seizure drugs. Unfortunately, this is the case for 30-40% of epilepsy patients. Active epilepsy imposes serious physical, cognitive, psychiatric and social consequences on patients and families. A more precise understanding of the cellular mechanism behind epilepsy could be a major step forward for developing drugs specifically directed against the epileptogenic process compared to the current mode of action reducing neuronal excitability in general throughout the brain’ says associate professor Lars Pinborg, head of the Danish Epilepsy Surgery Program at Rigshospitalet.

From ‘neuronal soup’ to single cell analysis

The study from the Khodosevich Group differs from previous work by using single cell analysis. Earlier studies on neuronal behavior in regards to epilepsy have taken a piece of the human brain and investigated all the neurons together as a group or a ‘neuronal soup.” When using this approach, diseased cells and healthy cells are mixed together, which makes it impossible to identify potential treatment targets.

“By splitting the neurons into many thousands of single cells, we can analyze each of them separately. From this huge number of single cells, we can pinpoint exactly what neurons are affected by epilepsy. We can even make a scale from least to most affected, which means that we can identify the molecules with the most promising potential to be effective therapeutic targets,” says Khodosevich.

Next step is to study the identified neurons and how their functional changes contribute to epileptic seizures. The hope is to then find molecules that can restore epilepsy related neuronal function back to normal and inhibit seizure generation.

Expanding knowledge on underlying mechanisms of epilepsy

The study confirms expression from key genes known from a number of previous studies, but is also a dramatic expansion of knowledge on the subject. Previously, gene expression studies have identified a couple of hundred genes that changes in epilepsy.

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