Tag Archives: lung

A protein in our pancreas and lungs could help treat asthma

Research using animal models and human tissue samples found a new potential avenue of treatment for asthma and chronic obstructive pulmonary disease (COPD).

Human alveolar tissue seen under the microscope.
Image credits Yale Rosen / Flickr.

An international research team reports that activation of a protein called free fatty acid receptor 4 (FFA4) in lung tissue can help reverse hallmark symptoms of asthma such as inflammation and obstruction of the airways in patients resistant to current treatments.

While the effect has not yet been confirmed in living human patients, the results warrant continued research into drugs that can target and interact with this protein, say the authors.

A breath of fresh air

“By the identification of this new mechanism we offer the hope for new effective medicines for those patients that are not responsive to our current treatments,” says Professor Christopher Brightling, an author on the paper from the University of Leicester.

The study identifies an existing class of medication that can interact with the FFA4 protein in model animals and human tissue samples to address the condition. FFA4 is found in cells in the gut and pancreas and helps to control blood glucose levels. Dietary fats, most notably omega 3 oils from fish, are known to activate this protein.

First, the team found that this protein is also present in lung tissues, which they called “surprising”. Furthermore, they found that activating FFA4 in mouse lung tissue causes smooth muscle surrounding the airways to relax, allowing more air to flow in. This effect also worked to reduce inflammation caused by exposure to pollution, cigarette smoke, or allergens. Cells in human lung tissue reacted in a similar way, they add.

Because this mechanism is different from the ones used for current asthma and COPD medication, it could prove to be an effective avenue of treatment for unresponsive or severe cases.

“It was indeed a surprise to find that by targeting a protein — which up to now has been thought of as being activated by fish oils in our diet — we were able to relax airway muscle and prevent inflammation,” says Andrew Tobin, Professor of Molecular Pharmacology at the University of Glasgow. “We are optimistic that we can extend our findings and develop a new drug treatment of asthma and COPD.”

With air pollution reaching worrying levels across the world, asthmatic patients are likely to see worsening symptoms. Such medication could help complement our current treatments to help preserve their health and quality of life.

The paper, “Pathophysiological regulation of lung function by the free fatty acid receptor FFA4,” has been published in the journal Science Translational Medicine.

COVID-19 asymptomatic cases may still develop lung damage

CT scan showing ground-glass opacity (GGO), similar to the kind of lesions in asymptomatic COVID-19 patients revealed by the new study. Credit: Mluisamtz11/Wikimedia CommonsCC BY-SA

One of the biggest conundrums surrounding COVID-19 is its astonishing variability of disease prognosis. Take two people of identical demographics and one of them might end up in the ICU while the other might not even have any symptoms to show. This unpredictability is what partly makes this virus extremely challenging to contain. Yet, even though COVID-19 positive cases may be asymptomatic, that doesn’t mean that organs are spared from damage ‘under the hood’.

In a new study, Chinese researchers at Wuhan University performed high-resolution CT scans on 58 asymptomatic patients with COVID-19 who showed evidence of pneumonia. They were diagnosed with fluorescence reverse-transcriptase-polymerase chain reaction (fRT-PCR) assays.

Among the asymptomatic patients, 27% went on to develop symptoms after admission about 3.7 days after their diagnosis. Their symptoms included fever, cough, fatigue, shortness of breath, and diarrhea.

However, all patients showed some lung abnormalities when their CT scans were analyzed in detail, regardless of whether they had symptoms or not.

Less than half of the patients presented bilateral lesions, and 58% showed unilateral lung lesions (either in the left or right lung).

“Lesions were fused to form patchy, crazy-paving signs, or diffusion pattern, distributed in multiple lung lobes or bilateral, and a few patients showed consolidation in CT imaging,” the researchers wrote in The Journal of Infection.

So, although some COVID-19 patients might look completely fine despite testing positive, they might be internally suffering from silent lung damage.

The different GGO manifestations in COVID-19 pneumonia patients.
A: single, pure GGO. B: Pleural parallel sign. C: Vascular thickening sign. D: Fine reticulation. E: Halo sign. F: Air bronchogram. Credit: The Journal of Infection.

These findings further complicate the picture of the pandemic, which scientists are still struggling to complete from scrambled jigsaw pieces.

What’s worrisome is that 30%-60% of COVID-19 pneumonia cases are among patients who had no symptoms or only mild symptoms. However, their ability to spread the virus is just as high as fully symptomatic cases. What’s more, the PCR tests used around the world to identify the coronavirus have a false-negative rate of up to 20%, meaning up to 1 in 5 people are wrongly told they don’t have the virus.

“In summary, CT images of asymptomatic cases with COVID-19 pneumonia have definite characteristics. Since the asymptomatic patients with COVID-19 is called “covert transmitter”, covert SARS-CoV-2 infections could be seeding new outbreaks, and some patients can progress rapidly in the short term,” the authors wrote in their study.

“Therefore, it is essential to pay attention to the surveillance of asymptomatic patients with COVID-19. CT examination plays a vital role in managing the current COVID-19 outbreak, for early detection of COVID-19 pneumonia, especially in the highly suspicious, asymptomatic cases with negative SARS-CoV-2 nucleic acid testing,” they concluded.

Credit: Pixabay.

Lung-inspired device produces clean fuel from water

Inspired by human lungs, researchers at Stanford University have created a bio-mimicking device that makes clean hydrogen fuel by splitting water molecules. The lung-like apparatus could improve the efficiency of fuel cells, which are used to power hydrogen vehicles or even cities.

Credit: Pixabay.

Credit: Pixabay.

By the time you finished reading the previous sentence, you must have inhaled and exhaled a couple of times, which didn’t even consciously register. But just because breathing is automatic doesn’t mean it’s simple. Our breathing system is consists of very sophisticated biological machinery that enables two-way gas exchange. When we breathe in, air moves through tiny pores called bronchioles until it reaches the alveoli —  small sacs at the end of the respiratory tree where carbon dioxide leaves the blood and oxygen enters it.

The alveoli have a unique structure composed of a micron-thick membrane that repels water on the inside but attracts it on the outer surface. This way, harmful bubbles are prevented from forming, allowing oxygen to pass into the bloodstream safely and highly efficiently.

Scientists at Stanford University mimicked the structure of the alveoli in order to come up with better electrocatalysts — materials that increase the rate of a chemical reaction at an electrode — for both electrolysis (splitting water into hydrogen and oxygen) and fuel cells (that run in reverse, ‘burning’ hydrogen for energy and outputting water as a byproduct).

“Clean energy technologies have demonstrated the capability of fast gas reactant delivery to the reaction interface, but the reverse pathway–efficient gas product evolution from the catalyst/electrolyte interface–remains challenging,” says Jun Li, the first author of the study.

The team led by Yi Cui, a professor of material science and engineering at Stanford, first made a 12-nanometer-thick plastic film with tiny pores on one side — this repels water. On the other side of the material, gold and platinum nanoparticles were added, which speed up chemical reactions. Finally, the film was rolled with the metal layer on the inside and sealed at the edges.

Gas exchange in mammalian lungs and the new Stanford system that turns water into fuel. Credit: Li et al. / Joule.

Gas exchange in mammalian lungs and the new Stanford system that turns water into fuel. Credit: Li et al. / Joule.

To demonstrate their system, the researchers first split water into its constituent parts: hydrogen and oxygen. The gases then traveled through the lung-like device without the energy costs of forming bubbles, unlike the carbon-based films that are usually used in fuel cells. This part of the process resembles exhalation.

That’s not all. Oxygen gas is delivered to a catalyst at the electrode surface, so it can be used as a reactant during electrochemical reactions. Through a reaction that consumes oxygen, energy can be generated. This process is akin to inhalation.

Ultimately, the lung-like apparatus was 32% more efficient at converting energy than the same membrane in a flat configuration, which highlights the importance of geometry.

What was particularly impressive was the system’s robustness and stability. The lung-like system retained 97% of its catalytic activity after 250 hours of use, whereas a conventional carbon-based membrane decayed to 74% in just 75 hours of activity.

All of these findings are extremely promising, although there is also room for improvement. The nano-polyethylene membrane used in the study degrades at temperatures higher than 100 degrees Celsius, making it unsuitable for a range of applications. The researchers are now trying out other nanoporous membranes that have better heat tolerance.

“The breathing-mimicking structure could be coupled with many other state-of-the-art electrocatalysts, and further exploration of the gas-liquid-solid three-phase electrode offers exciting opportunities for catalysis,” says Jun Li.

Credit: University of Texas Medical Branch at Galveston.

Scientists transplant lab-grown lungs into pigs — they worked fine

Credit: University of Texas Medical Branch at Galveston.

Credit: University of Texas Medical Branch at Galveston.

In a landmark study of regenerative medicine, researchers at the University of Texas Medical Branch (UTMB) have transplanted bioengineered lungs into adult pigs, with no visible complications. This puts us one step closer to providing human patients in dire need of a transplant with the organs they need to survive.

According to the U.S. Department of Health & Human Services, 20 people die each day waiting for a transplant. Lung transplants are particularly problematic, with the number of people requiring one increasing worldwide, while the number of available transplantable organs has decreased. Lungs are harvested from only 15 percent of all cadaveric donors, whereas kidneys and livers are harvested from 88 percent and hearts from 30 percent of deceased donors

The first human lung transplant procedure was performed in 1963, and the recipient survived 18 days, ultimately succumbing to renal failure and malnutrition. Over time, the number of lung transplant procedures has increased, and the operation is now an accepted treatment for end-stage lung disease. In 2015, there were 4,122 adult lung transplants reported — and that’s not nearly enough. But what if it was possible to grow new, personalized organs for each patient in need of a transplant? Certainly, thousands of lives would be saved each year — and, today, we’re nearing such a goal.

“Our ultimate goal is to eventually provide new options for the many people awaiting a transplant,” said Nichols, professor of internal medicine and associate director of the Galveston National Laboratory at UTMB.

For years, Joan Nichols and Joaquin Cortiella from The University of Texas Medical Branch at Galveston have been working on bioengineering lungs. In 2014, they were the first to grow lung cells in a lab, and their method has been refined ever since to the point that the team is now able to bioengineer transplantable lungs.

The challenges were numerous, of course. For one, in terms of different cell types, the lung is probably the most complex of all organs. For instance, the cells near the entrance are very different from those deep in the lung,

The procedure first starts with a support scaffold, a protein structure of collagen and elastin onto which the new lung will grow. The scaffold is placed in a tank filled with a solution made of nutrients and the pig’s own lung cells, following a carefully designed protocol.

For 30 days, the bioengineered lungs grew in a bioreactor before being transplanted into adult pigs. The medical condition of the animals was assessed at ten hours, two weeks, one month, and two months following the operation, which allowed the team to construct a timeline of the lung tissue’s development. For instance, in just two weeks, the transplanted lungs had established a stable network of blood vessels, which it needs in order to survive.

All of the pigs that received the bioengineered lung remained healthy.

“We saw no signs of pulmonary edema, which is usually a sign of the vasculature not being mature enough,” the researchers wrote. “The bioengineered lungs continued to develop post-transplant without any infusions of growth factors, the body provided all of the building blocks that the new lungs needed.”

This study was only meant to evaluate how well a bioengineered lung could adapt to an adult host organism, with positive results so far. However, the team did not measure how much oxygenation the lungs had provided, which will be researched in the future. And, if all goes well, Nichols and Cortiella hope to grow and transplant bioengineered lungs into people within 5 to 10 years. Besides transplants, bioengineered lungs are a great testing medium for experimental drugs, another line of work that can save countless lives.

“It has taken a lot of heart and 15 years of research to get us this far, our team has done something incredible with a ridiculously small budget and an amazingly dedicated group of people,” they wrote.

The findings appeared in the journal Science Translational Medicine.

Black lung disease makes resurgence among US coal miners

“This is history going in the wrong direction,” researchers say.

Progressive massive fibrosis (PMF), the most debilitating and deadly form of black lung disease, is increasing among US coal miners despite the implementation of dust controls decades ago, according to new research. Image credits: ATS.

Working in a coal mine is not an easy feat. The gruesome physical work, the closed spaces, and the lack of light makes for a hellish, unwelcoming environment. To top it all off, these miners often develop lung problems. The miners’ lung diseases weren’t well understood until the 1950s. Among these diseases, one was particularly prevalent: black lung disease.

Coal workers’ pneumoconiosis (CWP), commonly called black lung disease, is caused by long exposure to coal dust and can have devastating consequences. In 2013, CWP resulted in 25,000 deaths, but this was down from 29,000 deaths in 1990. Although it’s still a very big number, the trend seemed to be going down; seemed being the key word here.

In a new study, researchers analyzed U.S. Department of Labor data collected from former coal miners applying for benefits under the Federal Black Lung Program since the program began in 1970 until 2016. The start of the program coincides with the adoption of modern dust control measures in mines, which is when you’d expect the CWP numbers to go down.

That is, indeed, what was observed — until a point. In total, 4,679 coal miners were determined to have PMF, which was not unexpected. However, the numbers started to go up again in recent years. Black lung disease seems to be making a surprising resurgence.

“We were, however, surprised by the magnitude of the problem and are astounded by the fact that this disease appears to be resurging despite modern dust control regulations,” Dr. Almberg said. “This is history going in the wrong direction.”

Dr. Almberg said that it’s not exactly clear why this is happening, but there are a few possible explanations. Firstly, the affected miners appear to be working in smaller operations, which are less likely to invest in dust reduction systems.  Secondly, modern mines also produce higher levels of crystalline silica, which is even more damaging to the lungs than coal dust. Lastly, miners appear to be working longer hours and more days per week, which increases exposure and gives their bodies less time to recover. The last part adds an extra layer of serious concern regarding the miners’ health.

“In general, the higher concentration of dust, the more days worked per week, and the more years worked, the greater the risk,” she said. “It’s a classic dose-response relationship.”

In recent years, however, the US coal industry has embarked on a steady decline, being compensated and slowly replaced by renewable energy.  Despite President Trump’s campaign pledges, the coal industry is not making a resurgence — it’s simply not profitable, and too dirty. Black lung disease, however, appears to be on the rise.

The findings will be presented at the ATS 2018 International Conference.

sighing

This is how the brain makes you sigh every 5 minutes

Sighing is a fundamental biological reflex that’s a lot more important than most people care to think. We don’t just sigh when we’re in a position of weariness or relief, but quite regularly for no particular reason — about 12 times an hour. Sighing opens up the lungs, and is thus  vital to life. Now, researchers say they’ve found the neural pathways thatgovern the reflex. Those who suffer from breathing problems as well as compulsive sighers will benefit the most from the findings.

sighing

When we sigh, the million of tiny sacks inside the lungs called the alveoli inflate causing oxygen to enter and carbon dioxide to leave. Sometimes these sacks collapse and it takes a sigh to open them which is typically two breaths in for one breath out. If we didn’t sigh, we’d be dead in under an hour.

Joining forces, researchers from labs at  UCLA and Stanford sought to unravel the neural mechanism that leads to sighing. The researchers screen some 19,000 mouse genes that are involved in brain cells. They singled out 200 neurons in the brain stem that produce  one of two neuropeptides — small protein-like molecules (peptides) used by neurons to communicate with each other — but couldn’t tell at this point which were involved in sighing.

Later they found some peptides triggered a second set of 200 neurons, some of whom were already involved in controlling breathing. A handful of neurons were found to activate the mouse’s breathing muscles to produce a sigh — roughly 40 times an hour. When one of the peptides was blocked, the sighing rate was cut in half. Silencing both peptides halted sighing completely, the researchers reported in Nature.

“Sighing appears to be regulated by the fewest number of neurons we have seen linked to a fundamental human behavior,” explained Jack Feldman, a professor of neurobiology at the David Geffen School of Medicine at UCLA and a member of the UCLA Brain Research Institute. “One of the holy grails in neuroscience is figuring out how the brain controls behavior. Our finding gives us insights into mechanisms that may underlie much more complex behaviors.”

“Unlike a pacemaker that regulates only how fast we breathe, the brain’s breathing center also controls the type of breath we take,” Mark Krasnow, a professor of biochemistry and Howard Hughes Medical Institute Investigator at the Stanford University School of Medicine said. “It’s made up of small numbers of different kinds of neurons. Each functions like a button that turns on a different type of breath. One button programs regular breaths, another sighs, and the others could be for yawns, sniffs, coughs and maybe even laughs and cries.”

Drugs could be designed that target these peptides to either suppress or enhance their generation on a case by case basis. For instance, there are anxiety disorders and other psychiatric conditions where sighing grows debilitating. Conversely, in some cases poor breathing is caused by a poor sighing reflex. As for conscious sighing triggered by emotional states, this is still a subject for debate among scientists.

“There is certainly a component of sighing that relates to an emotional state. When you are stressed, for example, you sigh more,” Feldman said. “It may be that neurons in the brain areas that process emotion are triggering the release of the sigh neuropeptides — but we don’t know that.”

 

human-lung-organoid

First 3D mini lungs grow in the lab help end animal testing

human-lung-organoid

Image: University of Michigan Health System

Stem cells were coaxed to grow into 3D dimensional mini lungs, or  organoids, for the first time. These survived for more than 100 days. These pioneering efforts will serve to deepen our understanding of how lungs grow, as well as prove very useful for testing new drugs’ responses to human tissue. Hopefully, once human tissue grown in the lab becomes closer and close to the real deal (cultured hearts, lungs, kidneys etc.), animal testing might become a thing of the past.

Previously, lung tissue was only grown in  flat (2D) cell systems, basically on thin layers of cell cultures. Some 3D structures had also been developed by scientists, but these were made onto scaffolds from donated organs which had their cells removed. Of course, the organoids grown at the University of Michigan Medical School aren’t what you or me know as lungs. Since these were grown in a dish, the cells lack vital components like blood vessels, which facilitate the gas exchange during breathing. Nevertheless, components like large airways known as bronchi and small lung sacs called alveoli were successfully grown. These 3-D structures are the closest we’ve come to a lab grown lung, according to the paper published in eLife.

To make the lung organoids, the team manipulated  signaling pathways that control the formation of organs.

  1. Stem cells were instructed to form a type of tissue called endoderm, found in early embryos and that gives rise to the lung, liver and several other internal organs.
  2. Scientists activated important development pathways that are known to make endoderm form three-dimensional tissue while inhibiting two other key development pathways at the same time.
  3. Acellular human lung matrix was seeded with spheroids and cultured for 40 days. Resulting matrices had abundant proximal airway-like structures (scale bar 10 μM) (credit: Briana R. Dye et al./eLife)

    Acellular human lung matrix was seeded with spheroids and cultured for 40 days. Resulting matrices had abundant proximal airway-like structures (scale bar 10 μM) (credit: Briana R. Dye et al./eLife)

    The endoderm became tissue that resembles the early lung found in embryos.

  4. This early lung-like tissue spontaneously formed three-dimensional spherical structures as it developed.
  5. To make these structures expand and develop into lung tissue, the team exposed the cells to additional proteins that are involved in lung development.
  6. The resulting lung organoids survived in the lab for more than 100 days.

“These mini lungs can mimic the responses of real tissues and will be a good model to study how organs form, change with disease, and how they might respond to new drugs,” says senior study author Jason R. Spence, Ph.D., assistant professor ofinternal medicine and cell and developmental biology at the University of Michigan Medical School.

“We expected different cells types to form, but their organization into structures resembling human airways was a very exciting result,” says lead study author Briana Dye, a graduate student in the U-M Department of Cell and Developmental Biology.

 

 

lung_cancer

Newly discovered microRNA may help diagnose lung cancer

lung_cancer

Photo: drugdiscovery.com

Researchers at the National Research Foundation of Korea report on Sunday that they have identified a new microRNA molecule that suppresses a gene, which previous research had identified as playing a crucial role in lung cancer development. If the present findings are refined, it may be possible to diagnose lung cancer in the future based on this genetic marker.

MicroRNAs constitute a recently discovered class of non-coding RNAs that play key roles in the regulation of gene expression. Acting at the post-transcriptional level, these fascinating molecules may fine-tune the expression of as much as 30% of all mammalian protein-encoding genes. Their aberrant expression may be involved in human diseases, including cancer, as shown by previous research that found aberrant microRNA is linked to leukemia or breast cancer.

The Korean researchers identified one such  small chain of RNA, called miR-9500, which forms a stem-loop structure and becomes expressed in lower levels in cancer tissue, compared to normal tissue. They also found that miR-9500 directly suppressed Akt1, which is assumed to be its target gene, as demonstrated via western blot, but did not affect the corresponding mRNA levels. Akt1 plays an important role in the production and proliferation of lung cancer genes, the study found.

To prove their point,  Korean scientists infected a mouse with lung cancer and gave it miR-9500 injections over the next six weeks. They found that the rate of metastasis of a tumor in a mouse that had been injected with miR-9500 was significantly lower than that of a tumor growing in a normal mouse.

This sort of investigations will be extremely interesting to follow in the future, especially if a team can come up with a way of viably diagnosing human lung cancer based on miR-9500 expression levels. Already, the research may have some flaws, however. For one, the initial  flank tumor proliferation experiment may be irrelevant, since the flank isn’t the native environment for human cancer cells. Secondly, the researchers performed direct injections into the tumor site with their miR, which kind of defeats the purpose of the experiment – you want to see if the molecule lives long enough in the blood stream until it reaches the target tumor. Then, tumor size sample data wasn’t particularly significant to become extremely valid from a statistical standpoint.

Either way, follow-up studies will be much welcome. The findings were reported in the journal Cell Death and Differentiation.

Inserting oxygen into the bloodstream directly

Injecting oxygen filled particles lets you survive without breathing

Inserting oxygen into the bloodstream directly

Photo: Ocean Networks Canada

Without oxygen, your brain would shutdown within five minutes or so and you, as a person, along with it. Deprived of this fundamental element, brain cells can’t produce energy anymore and wither and die. Breathing is important, that’s pretty settled but what happens if you can’t rely on your lungs anymore. A team of researchers led by Harvard Medical School’s John N. Kheir found that oxygen-deprived patients can survive if an intravenous injection of gas-filled microparticles is made. These patients, however, were in fact oxygen-starved rabbits, but ultimately this should be made to work on humans.

At the turn of the last century, if your lungs failed or became clogged, you would had been pretty much done for. The advent of a sound technique for cardiopulmonary resuscitation in the 1950s changed all that, but even in the 21st century there’s little doctors can do in the face of oxygen deprivation. The Harvard research could come as a game changer, and help patients survive a critical period, buying time for live-saving medical procedures.

The experiment involved injecting microparticles  tiny capsules (2-4 micrometers tiny) made of a single layer of lipids surrounding a small bubble of oxygen gas.  The bubbles are in turn suspended in a liquid to keep them from joining and becoming too thick, which have had the opposite desired effect. Upon injection, the capsules crash into red cells in the blood, transferring the oxygen to the cells. Tests on rabbits with blocked windpipes show that up to 70% of the injected oxygen makes it way into the bloodstream. The rabbits were kept alive for up to fifteen minutes.

Fifteen minutes might not seem like much, but it may be enough for doctors to perform a quick surgery to your lungs or other vital oxygen delivery tissues in your body. And it doesn’t stop here, either. Global oxygen deprivation means death, but there are also localized forms of oxygen deprivation. A lack of blood flow to the eyes, for instance, can lead to blindness before doctors even realize there’s anything wrong. Using a similar method, Swiss doctors delivered  oxygen-sniffing micro robots  into the retinas of glaucoma patients to determine if and where the oxygen supply had been cut off. This greatly improves treatment time, lowering the likelihood of permanent damage to the patient’s vision.

What about surviving without oxygen at all in your system; without blood in the system for that matter. This blasphemous concept is called suspended animation and is a reality.

microfluid_printed_tube

Bioprinting tissue: a solution for faster, cheaper drug testing

Here on ZME Science we’ve written extensively about various breakthrough medical research, some of which promising cures for various mental or physiological conditions. Most of these findings come from pre-clinical trials, however, where animal models are used. The thing is, while a drug might work to cure a lung disease in a mouse, it could very well prove to be useless in humans. In fact, some 70% of investigational new drugs fail to show efficacy in human trials, adding to the $4 billion a piece or ten years worth development typically required to put a drug on the market. All this time, energy and expenditure are then transferred to the patient, who has to pay for all of this.

microfluid_printed_tube

A 3D-printed tube dyed for clarity. This is a simple demonstration that was printed with a single printer nozzle being fed by two different materials. The microfluidic print head sequenced the two materials into the banded structure. (Credit: Aspect Biosystems)

Besides animal models, medical researchers rely on 2-D cultures in petri dishes, but these cannot model the complex 3D intercellular interactions occurring in our organs, and animals are poor predictors of the human drug response. Some work, some don’t, so it’s a hit and miss game at the moment. The genuine problem is that there are too many misses.

One way to solve this is to perform drug tests directly on human tissues. No, not on actually living, breathing humans or clones, but on 3-D bioprinted tissue. This is what University of British Columbia Department of Electrical and Computer Engineering researchers and spinoff Aspect Biosystems are currently working on.

“There are 200 ways to cure pulmonary fibrosis in mice but not a single cure for the disease in humans,” says Sam Wadsworth, co-founder and director of biology of Aspect Biosystems. He and his colleagues have discovered a technique for growing 3D human airway tissues that almost exactly replicate the lung wall. Compared to the standard technique of growing sheets of cells in a dish or test tube, this is a major improvement, he says.

“We use our airway cultures to model a disease where the animal models have been poor predictors for drug discovery,” says Wadsworth, who is also a research associate at the Institute for Heart and Lung Health at St. Paul’s Hospital, where he works on the BRONCH project. “Pulmonary fibrosis is a rare but terrible disease. If you don’t get a transplant, you’ll die.”

By now 3-D printing isn’t an innovation anymore, but 3-D printing live tissue — well that’s another story. UBC’s technique works much in the same way as any regular 3-D printer: layer-by-layer fabrication. However, the material isn’t some smooshy polymer compound, but living human cells, extracellular matrix material, and other factors. The tough part was arranging the printer’s head to be able to shift through various types of cells as it performed the cell layering process.

The researchers solved this by incorporating microfluidic technology into the print head allowing them to manipulate the printed materials in a unique way, including the sequencing of different cell types, and the ability to generate complex arrangements of the materials prior to deposition. That is, the composition of one of the base printing units (a fiber) is not restricted to just one material, but can have a programmed composition including many different materials (in this case the different materials are different types of human cells).

There is more 3D bioprinting tech developed elsewhere, however, UBC’s approach is unique in this respect since their solution was designed from the ground up. So far, simple 3D tissues are being created meant for testing by pharmaceutical companies. As the process becomes more refined, it may be possible for the solution to become fully integrated iintodrug testing processes and dramatically reduce R&D costs.

“We are currently working with customers on a one-on-one basis and expect to have products online over the next two to three years. We currently do not have plans to release the printing technology itself as a product, but will rather be providing printed tissue structures in a multi-well plate format,” the researchers state in a press release.

Odor receptors discovered in lungs

Researchers at Washington University in St. Louis and the University of Iowa have found out that we don’t just smell with our noses, we also smell with our lungs… sort of. But while your nose might tell you that something is or isn’t good for you, your lungs might make you cough it out.

Smelling with your lungs

“They’re beautiful cells,” said Ben-Shahar, of the pulmonary neuroendocrine cells he has been studying in lung tissues. The flask-like cells that are full of serotonin (stained green here) and other chemicals extend processes up through the epithelial cells (purple) lining the airways to monitor the chemical makeup of each breath. The top part of the image is a plan view of the airway lining and the bottom part is a section through the lining.

“They’re beautiful cells,” said Ben-Shahar, of the pulmonary neuroendocrine cells he has been studying in lung tissues. The flask-like cells that are full of serotonin (stained green here) and other chemicals extend processes up through the epithelial cells (purple) lining the airways to monitor the chemical makeup of each breath.

The odor receptors in your lungs are very different from those in your nose. Instead of being located in the membranes of nerve cells, they are located in neuroendocrine cells – cells that receive neuronal input and send out hormones to the blood. So basically, instead of sending out a nerve signal that allows your brain to ‘read’ the smell, they dump hormones that make your airways constrict.

It comes as quite a surprise that an entire class of odor receptors went undetected for so long.

“We forget,” said Yehuda Ben-Shahar, PhD, assistant professor of biology, in Arts & Sciences, and of medicine at Washington University in St. Louis, “that our body plan is a tube within a tube, so our lungs and our gut are open to the external environment. Although they’re inside us, they’re actually part of our external layer. So they constantly suffer environmental insults,” he said, “and it makes sense that we evolved mechanisms to protect ourselves.”

To put it simply, pulmonary neuroendocrine cells, or PNECs are guards, whose job is to make sure nothing harmful enters your lungs. If for any reason, they defect, this could lead to a broad range of afflictions, such as chronic obstructive pulmonary disease (COPD) and asthma. Patients with these diseases are told to avoid traffic fumes, pungent odors, perfumes and similar irritants, which can trigger airway constriction and breathing difficulties.

Every breath you take

A diagram of the airway lining suggests how the pulmonary neuroendocrine cells (red) trigger a response to inhaled chemicals. When a chemical (orange triangle) docks on a receptor (black) they dump secretory chemicals (thin orange arrows), which have an immediate but localized effect on muscles (blue) and nerves (pink), possibly triggering responses such as a cough. Copyright: Ben Sahar.

A diagram of the airway lining suggests how the pulmonary neuroendocrine cells (red) trigger a response to inhaled chemicals. When a chemical (orange triangle) docks on a receptor (black) they dump secretory chemicals (thin orange arrows), which have an immediate but localized effect on muscles (blue) and nerves (pink), possibly triggering responses such as a cough. Copyright: Ben Sahar.

Earlier, a team at the University of Iowa, where Ben-Shahar was a postdoctoral research associate, studied genes expressed by patches of tissue from lung transplant donors. They found a ciliated group of cells that could perceive bitter smells and kick it out, if found dangerous. But people are vulnerable to more than just bitter smells, so Ben-Shahar decided to look again. This time he found that these tissues also express odor receptors, not on ciliated cells but instead on neuroendocrine cells – and this made a lot of sense.

“When people with airway disease have pathological responses to odors, they’re usually pretty fast and violent,” said Ben-Shahar. “Patients suddenly shut down and can’t breathe, and these cells may explain why.”

(C) Nature Biotechnology

First functioning lung and airway cells grown from human stem cells

Biotechnology is growing fast and the findings researchers are making the field are nothing short of breathtaking. Previously, ZME Science reported in the past few years alone a series of milestone premiers: the first bioengineered kidney and 3-D human kidney cells, the  first functioning blood vessels, the first teeth-like structures, a bioengineered heart that beats on its own and many more. All of these vital tissue and precursor organs were grown in the lab using stem cells or induced pluripotent stem cells. Now, yet another milestone confirms the growing trend after researchers at Columbia University Medical Center reported they’ve created functioning lung and airway cells.

(C) Nature Biotechnology

(C) Nature Biotechnology

Lung transplants are among the most complicated medical procedures, and patients have one of the poorest prognosis post-transplant. This is because it’s very difficult to find biocompatible lungs for transplant. Growing new lungs in the lab directly from patients’ cells, however, offers a massive workaround. More or less, the resulting lung would be very similar to the one the patient loses during transplant, greatly reducing the chance the immune system will reject the lung. Growing organs may seem like SciFi and although we’re still far away from seeing a fully fledged, lab-grown organ becoming successfully transplanted, we’re getting there.

“Now, we are finally able to make lung and airway cells,” study leader Dr. Hans-Willem Snoeck, a professor of microbiology and immunology at Columbia University in New York, said in a statement.

A breath of fresh air

Previously, Snoeck and team discovered a set of chemical factors that can turn human embryonic stem (ES) cells or human induced pluripotent stem (iPS) cells (adult skin cells that have been reprogrammed into stem cells) into anterior foregut endoderm – precursors of lung and airway cells.  Now, the same researchers have found a set of chemicals that coax stem cells in growing into epithelial cells which coat the surface of lungs.

In fact, resultant cells were found to express markers of at least six types of lung and airway epithelial cells, particularly markers of type 2 alveolar epithelial cells. The kind of cells are vital because they produce  surfactant, a substance critical to maintain the lung alveoli, where gas exchange takes place; they also participate in repair of the lung after injury and damage.

 “Now, we are finally able to make lung and airway cells. This is important because lung transplants have a particularly poor prognosis. Although any clinical application is still many years away, we can begin thinking about making autologous lung transplants — that is, transplants that use a patient’s own skin cells to generate functional lung tissue,” said the authors of the paper published in the journal Nature Biotechnology.

Transplants may be long away, but lab-grown lungs from diseased patients could serve a much more immediate purpose in the future. Early-stage precursor lungs could become highly valuable in research, where they could act as biological test beds for various types of drugs or kinds of treatment. This applies for virtually any kind of organ. Even in this primitive stage, testing could be made. For instance, idiopathic pulmonary fibrosis (IPF) is a lung disease  in which type 2 alveolar epithelial cells are thought to play a central role.

“No one knows what causes the disease, and there’s no way to treat it,” says Dr. Snoeck. “Using this technology, researchers will finally be able to create laboratory models of IPF, study the disease at the molecular level, and screen drugs for possible treatments or cures.”

“In the longer term, we hope to use this technology to make an autologous lung graft,” Dr. Snoeck said. “This would entail taking a lung from a donor; removing all the lung cells, leaving only the lung scaffold; and seeding the scaffold with new lung cells derived from the patient. In this way, rejection problems could be avoided.” Dr. Snoeck is investigating this approach in collaboration with researchers in the Columbia University Department of Biomedical Engineering.

“I am excited about this collaboration with Hans Snoeck, integrating stem cell science with bioengineering in the search for new treatments for lung disease,” said Gordana Vunjak-Novakovic, PhD, co-author of the paper and Mikati Foundation Professor of Biomedical Engineering at Columbia’s Engineering School and professor of medical sciences at Columbia University College of Physicians and Surgeons.